Anti-Malarial Compounds

ABSTRACT

The present invention provides tricyclic compounds, arylamide compounds, and other compounds, and compositions comprising the same, for treating malaria, and methods of treating malaria comprising administering such compounds to an animal.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.provisional application Ser. No. 61/162,467 filed Mar. 23, 2009 and toU.S. provisional application Ser. No. 61/083,972 filed Jul. 28, 2008,each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed, in part, to tricyclic compounds,arylamide compounds, and other compounds, and compositions comprisingthe same, for treating malaria, and methods of treating malariacomprising administering such compounds to an animal.

BACKGROUND OF THE INVENTION

World-wide, 41% of the population live in areas where malaria istransmitted, such as parts of Africa, Asia, Middle East, Central andSouth America, Hispaniola, and Oceania. Each year between 350 and 500million cases of malaria occur worldwide, and over one million peopledie, most of them young children in sub-Saharan Africa. In areas ofAfrica with high malaria transmission, an estimated 990,000 people diedof malaria in 1995. In 2002, malaria was the fourth cause of death inchildren in developing countries. In addition, malaria caused 10.7% ofall children's deaths in developing countries.

Antimicrobial peptides (AMPs) represent a component of the innate immunesystem that provides resistance to a variety of pathogenic bacteria.AMPs have provided new leads for developing antibiotics, because theyplay a central role in the innate immune system. Some AMPs display verybroad spectrum action against bacteria, yeast, fungus, and even viruses.Anti-parasitic activities have also been reported for a number of hostdefense peptides. The best studied organisms include Plasmodium,Leishmania, and Trypanosoma (Vizioli et al., Trends in Pharmacol., 2002,18, 475-476; Jacobs et al., Antimicrob. Agents Chemother., 2003, 47,607-613; and Brand et al., J. Biol. Chem., 2002, 277, 49332-49340), theparasitic agents of malaria, leishmaniasis and Chagas' disease,respectively. Additional protozoan parasites reported to be killed bythe host defense peptides are Cryptosporidium (Giacometti et al.,Antimicrob. Agents Chemother., 2000, 44, 3473-3475) and Giardia (Aley etal., Infect. Immun., 1994, 62, 5397-5403), human pathogens transmittedin contaminated drinking water. The peptides appear to kill protozoa byinteracting with the cytoplasmic membrane causing excessivepermeability, lysis and death; a mechanism which is similar to theirmechanism of action against bacteria. Specificity for the parasiteversus the host cell can be attributed to differences in phospholipidcontent and the lack of cholesterol in the protozoan membrane. Becausethe site of action is at the membrane and not to any specific receptoror intracellular target, the development of resistance to the cytotoxicproperties of the antimicrobial peptides is highly unlikely.

With regard to anti-malarial activities, natural host defense proteinsand their analogs have been shown to inhibit oocyst development ofseveral Plasmodium species in various mosquito hosts (Gwadz et al.,Infect. Immun., 1989, 57, 2628-2633; and Possani et al., Toxicon, 1998,36, 1683-1692) and are directly cytotoxic against early sporogonicstages of Plasmodium in cell culture (Arrighi et al., Antimicrob. AgentsChemother., 2002, 46, 2104-2110). Furthermore, several antimicrobialpeptides have been identified which selectively kill intraerthrocyticparasites (plasmodia life forms growing in red blood cells) by eitherattacking the infected erythrocyte while sparring normal erthrocytes(Feder et al., J. Biol. Chem., 2000, 275, 4230-4238; and Krugliak etal., Antimicrob. Agents Chemother., 2000, 44, 2442-2451) or interactingwith and killing the intracellular parasite without harming the infectedred blood cell (Dagan et al., Antimicrob. Agents Chemother., 2002, 46,1059-1066; and Efron et al., J. Biol. Chem., 2002, 277, 24067-24072).Recognizing the significant therapeutic limitations of peptides, thedevelopment of nonpeptidic mimics of these anti-plasmodia peptides wouldrepresent a novel and powerful therapy to combat malaria.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I:

wherein: X is C(R⁷)C(R⁸), C(═O), N(R⁹), O, S, S(═O), or S(═O)₂; R⁷, R⁸,and R⁹ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, oraromatic group; R¹ and R² are, independently, H, C₁-C₈alkyl,C₁-C₈alkoxy, halo, OH, haloC₁-C₈alkyl, or CN; R³ and R⁴ are,independently, carbocycle(R⁵)(R⁶); each R⁵ and each R⁶ are,independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, aromaticgroup, heterocycle, or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or a pharmaceutically acceptable saltthereof, and compositions comprising the same and a pharmaceuticallyacceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula I:

wherein: X is C(R⁷)C(R⁸), C(═O), N(R⁹), O, S, S(═O), or S(═O)₂; R⁷, R⁸,and R⁹ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, oraromatic group; R¹ and R² are, independently, H, C₁-C₈alkyl,C₁-C₈alkoxy, halo, OH, haloC₁-C₈alkyl, or CN; R³ and R⁴ are,independently, carbocycle(R⁵)(R⁶); each R⁵ and each R⁶ are,independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, aromaticgroup, heterocycle, or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or a pharmaceutically acceptable saltthereof.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula I:

wherein: X is C(R⁷)C(R⁸), C(═O), N(R⁹), O, S, S(═O), or S(═O)₂; R⁷, R⁸,and R⁹ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, oraromatic group; R¹ and R² are, independently, H, C₁-C₈alkyl,C₁-C₈alkoxy, halo, OH, haloC₁-C₈alkyl, or CN; R³ and R⁴ are,independently, carbocycle(R⁵)(R⁶); each R⁵ and each R⁶ are,independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, aromaticgroup, heterocycle, or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or a pharmaceutically acceptable saltthereof.

The present invention also provides compounds of Formula II:

wherein: X is O or S; each Y is, independently, O, S, or N; each R¹ is,independently, H, 5- or 6-membered heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each R¹ is, independently, together with Y a5- or 6-membered heterocycle; each R² is, independently, H, CF₃,C(CH₃)₃, halo, or OH; and each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof, and compositions comprisingthe same and a pharmaceutically acceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula II:

wherein: X is O or S; each Y is, independently, O, S, or N; each R¹ is,independently, H, 5- or 6-membered heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each R¹ is, independently, together with Y a5- or 6-membered heterocycle; each R² is, independently, H, CF₃,C(CH₃)₃, halo, or OH; and each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula II:

wherein: X is O or S; each Y is, independently, O, S, or N; each R¹ is,independently, H, 5- or 6-membered heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each R¹ is, independently, together with Y a5- or 6-membered heterocycle; each R² is, independently, H, CF₃,C(CH₃)₃, halo, or OH; and each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.

The present invention also provides compounds of Formula III:

Q-X—Z—X-Q

wherein: Z is

or phenyl; each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4; each X is, independently, O, S, or N; each R¹ is, independently, H,CF₃, C(CH₃)₃, halo, or OH; each R³ is, independently, H, —NH—R²,(CH₂)_(r)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R² is, independently, H,or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R⁴is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and each R⁵ is, independently, H or CF₃; or a pharmaceuticallyacceptable salt thereof, and compositions comprising the same and apharmaceutically acceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula III:

Q-X—Z—X-Q

wherein: Z is

or phenyl; each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4; each X is, independently, O, S, or N; each R¹ is, independently, H,CF₃, C(CH₃)₃, halo, or OH; each R³ is, independently, H, —NH—R²,—(CH₂)_(r)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R² is, independently, H,or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R⁴is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and each R⁵ is, independently, H or CF₃, or a pharmaceuticallyacceptable salt thereof.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula III:

Q-X—Z—X-Q

wherein: Z is

or phenyl; each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4; each X is, independently, O, S, or N; each R¹ is, independently, H,CF₃, C(CH₃)₃, halo, or OH; each R³ is, independently, H, —NH—R²,—(CH₂)_(r)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R² is, independently, H,or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R⁴is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and each R⁵ is, independently, H or CF₃, or a pharmaceuticallyacceptable salt thereof.

The present invention also provides compounds of Formula IV:

wherein: G is

each X is, independently, O or S; each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R²is, independently, H, C₁-C₈alkyl, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R³ is, independently, H, CF₃, C(CH₃)₃, halo,or OH; and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4, or apharmaceutically acceptable salt thereof, and compositions comprisingthe same and a pharmaceutically acceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula IV:

wherein: G is

each X is, independently, O or S; each R¹ is, independently

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R²is, independently, H, C₁-C₈alkyl, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R³ is, independently, H, CF₃, C(CH₃)₃, halo,or OH; and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4, or apharmaceutically acceptable salt thereof.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula IV:

wherein: G is

each X is, independently, O or S; each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R²is, independently, H, C₁-C₈alkyl, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R³ is, independently, H, CF₃, C(CH₃)₃, halo,or OH; and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4, or apharmaceutically acceptable salt thereof.

The present invention also provides compounds of Formula V:

wherein: each X is, independently, O, S, or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is,independently, 1 or 2; each R² is, independently, H, halo, CF₃, orC(CH₃)₃; and each V² is H, and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; or a pharmaceutically acceptable saltthereof, and compositions comprising the same and a pharmaceuticallyacceptable carrier, provided that the compound is not:a)

b)

orc)

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula V:

wherein: each X is, independently, O, S, or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or—(CH₂)_(n)—NH—C(═O)—R⁴ where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is,independently, 1 or 2; each R² is, independently, H, halo, CF₃, orC(CH₃)₃; and each V² is H, and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; or a pharmaceutically acceptable saltthereof.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula V:

wherein: each X is, independently, O, S, or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or—(CH₂)_(n)—NH—C(═O)—R⁴ where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is,independently, 1 or 2; each R² is, independently, H, halo, CF₃, orC(CH₃)₃; and each V² is H, and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; or a pharmaceutically acceptable saltthereof.

The present invention also provides compounds of Formula VI:

wherein: each Y is, independently, O, S, or NH; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; and each R² is, independently, H, halo, CF₃,or C(CH₃)₃; or a pharmaceutically acceptable salt thereof, andcompositions comprising the same and a pharmaceutically acceptablecarrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula VI:

wherein: each Y is, independently, O, S, or NH; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; and each R² is, independently, H, halo, CF₃,or C(CH₃)₃; or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula VI:

wherein: each Y is, independently, O, S, or NH; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; and each R² is, independently, H, halo, CF₃,or C(CH₃)₃; or a pharmaceutically acceptable salt thereof.

The present invention also provides method of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula VII:

wherein: each R¹ is, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo,OH, CF₃, or CN; each R² is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula VII:

wherein: each R¹ is, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo,OH, CF₃, or CN; each R² is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.

The present invention also provides compounds of Formula VIII:

wherein: D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and each X is, independently, O or S, or a pharmaceutically acceptablesalt thereof, and compositions comprising the same and apharmaceutically acceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula VIII:

wherein: D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and each X is, independently, O or S, or a pharmaceutically acceptablesalt thereof.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula VIII:

wherein: D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and each X is, independently, O or S, or a pharmaceutically acceptablesalt thereof.

DESCRIPTION OF EMBODIMENTS

Collectively and individually, each of the compounds described hereinare also referred to herein as “anti-malarial compounds.”

As used herein and unless otherwise indicated, the term “animal” isintended to include, but not be limited to, humans and non-humanvertebrates such as wild, domestic and farm animals.

As used herein and unless otherwise indicated, the term “about” isintended to mean±5% of the value it modifies. Thus, about 100 means 95to 105.

As used herein and unless otherwise indicated, the term “alkyl” isintended to include branched and straight-chain saturated aliphatichydrocarbon groups having the specified number of carbon atoms. Forexample, C₁-C₈, as in “C₁-C₈ alkyl” is intended to include groups having1, 2, 3, 4, 5, 6, 7, or 8 carbons in a linear or branched arrangement.“C₁-C₆ alkyl” is intended to include groups having 1, 2, 3, 4, 5, or 6carbons in a linear or branched arrangement. “C₁-C₃ alkyl” is intendedto include groups having 1, 2, or 3 carbons in a linear or branchedarrangement. Examples of alkyl groups include, but are not limited to,methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl,2-methyl-1-propyl, 2-methyl-2-propyl, pentyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, isopentyl,neopentyl, hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, heptyl, and octyl, or any combination thereof. An alkylgroup can be unsubstituted or substituted with one, two, or threesuitable substituents. These same alkyl groups can be used in connectionwith “alkoxy” groups, “haloalkyl” groups, “alkenyl” groups, “alkynyl”groups, and “cycloalkyl” groups as appropriate.

As used herein and unless otherwise indicated, the term “halo” meansfluorine, chlorine, bromine, or iodine.

As used herein and unless otherwise indicated, the phrase “5- or6-membered heterocycle” means a monocyclic ring comprising carbon atoms,hydrogen atoms, and one or more heteroatoms, such as 1 to 3 heteroatoms,independently chosen from nitrogen, oxygen, and sulfur. 5-memberedheterocycles include, but are not limited to, thienyl, 2-thienyl,3-thienyl, furyl, 2-furyl, 3-furyl, pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,imidazolyl, pyrazolyl, isothiazolyl, pyrrolinyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, and pyrazolinyl. 6-membered heterocyclesinclude, but are not limited to, pyranyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, piperidyl, piperazinyl, and morpholinyl. The5- and 6-membered heterocycles can be unsubstituted or substituted withone, two, or three suitable substituents.

As used herein and unless otherwise indicated, the phrase “carbocycle”means a 5- or 6-membered, saturated or unsaturated cyclic ring,optionally containing O, S, or N atoms as part of the ring. Examples ofcarbocycles include, but are not limited to, cyclopentyl, cyclohexyl,cyclopenta-1,3-diene, phenyl, and any of the heterocycles recited above.

As used herein and unless otherwise indicated, the term “phenyl” means—C₆H₅. A phenyl group can be unsubstituted or substituted with one, two,or three suitable substituents.

As used herein and unless otherwise indicated, the phrase“therapeutically effective amount” of a composition or compound ismeasured by the therapeutic effectiveness of the administered compound,wherein at least one adverse effect is ameliorated or alleviated. Thetherapeutic effect is dependent upon the disorder being treated or thebiological effect desired. As such, the therapeutic effect can be adecrease in the severity of symptoms associated with the disorder and/orinhibition (partial or complete) of progression of the disorder, orimproved treatment, healing, prevention or elimination of a disorder, orside-effects. The amount needed to elicit the therapeutic response canbe determined based on the age, health, size and sex of the subject.Optimal amounts can also be determined based on monitoring of thesubject's response to treatment.

When administered to a mammal (e.g., to an animal for veterinary use orto a human for clinical use) the anti-malarial compounds describedherein can be administered in isolated form. As used herein and unlessotherwise indicated, the term “isolated” means that the anti-malarialcompounds described herein are separated from other components of either(a) a natural source, such as a plant or cell, such as a bacterialculture, or (b) a synthetic organic chemical reaction mixture, such asby conventional techniques.

As used herein and unless otherwise indicated, the term “purified” meansthat when isolated, the isolate contains at least 90%, at least 95%, atleast 98%, or at least 99% of an anti-malarial compound described hereinby weight of the isolate.

As used herein and unless otherwise indicated, the phrase“pharmaceutically acceptable salt(s),” includes, but is not limited to,salts of acidic or basic groups. Compounds that are basic in nature arecapable of forming a wide variety of salts with various inorganic andorganic acids. Acids that may be used to prepare pharmaceuticallyacceptable acid addition salts of such basic compounds are those thatform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions including, but not limited to,sulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide,hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, acid citrate,tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds thatinclude an amino moiety may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above. Compoundsthat are acidic in nature are capable of forming base salts with variouspharmacologically acceptable cations. Examples of such salts include,but are not limited to, alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium lithium, zinc, potassium, andiron salts.

As used herein and unless otherwise indicated, the phrase “suitablesubstituent” means a group that does not nullify the synthetic orpharmaceutical utility of the anti-malarial compounds described hereinor the intermediates useful for preparing them. Examples of suitablesubstituents include, but are not limited to: (C₁-C₆)alkyl,(C₁-C₆)alkenyl, (C₁-C₆)alkynyl, (C₅-C₆)aryl, (C₃-C₅)heteroaryl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy, (C₅-C₆)aryloxy, —CN, —OH, oxo, halo,—NO₂, —CO₂H, —NH₂, —NH((C₁-C₈)alkyl), —N((C₁-C₈)alkyl)₂, —NH((C₆)aryl),—N((C₅-C₆)aryl)₂, —CHO, —CO((C₁-C₆)alkyl), —CO((C₅-C₆)aryl),—CO₂((C₁-C₆)alkyl), and —CO₂((C₅-C₆)aryl). One of skill in art canreadily choose a suitable substituent based on the stability andpharmacological and synthetic activity of the anti-malarial compoundsdescribed herein.

As used herein and unless otherwise indicated, the terms “treatment” or“treating” refers to an amelioration of malaria, or at least onediscernible symptom thereof. In another embodiment, “treatment” or“treating” refers to an amelioration of at least one measurable physicalparameter, not necessarily discernible by the patient. In yet anotherembodiment, “treatment” or “treating” refers to inhibiting theprogression of malaria, either physically, e.g., stabilization of adiscernible symptom, physiologically, e.g., stabilization of a physicalparameter, or both. In yet another embodiment, “treatment” or “treating”refers to delaying the onset of malaria.

In some embodiments, the anti-malarial compound, or compositioncomprising the same, are administered to a patient, such as a human, asa preventative measure against malaria. As used herein and unlessotherwise indicated, “prevention” or “preventing” refers to a reductionof the risk of acquiring malaria.

The anti-malarial compounds described herein may contain one or morechiral centers and/or double bonds and, therefore, exist asstereoisomers, such as double-bond isomers (i.e., geometric isomers),enantiomers, or diastereomers. Therefore, the anti-malarial compoundsdescribed herein encompass all of the corresponding compound'senantiomers and stereoisomers, that is, both the stereomerically pureform (e.g., geometrically pure, enantiomerically pure, ordiastereomerically pure) and enantiomeric and stereoisomeric mixtures.Enantiomeric and stereoisomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers andstereoisomers can also be obtained from stereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

The present invention provides compounds of Formula I:

wherein:

X is C(R⁷)C(R⁸), C(═O), N(R⁹), O, S, S(═O), or S(═O)₂;

R⁷, R⁸, and R⁹ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,CF₃, or aromatic group;

R¹ and R² are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,haloC₁-C₈alkyl, or CN;

R³ and R⁴ are, independently, carbocycle(R⁵)(R⁶);

each R⁵ and each R⁶ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy,halo, OH, CF₃, aromatic group, heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is N(R⁹), O, S, or S(═O)₂; or X is NH, O, or S;or X is NH or S.

In any of the above embodiments, R¹ and R² are, independently, H,C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, haloC₁-C₃alkyl, or CN; or R¹ and R²are, independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, or OH; or R¹ andR² are, independently, H, C₁-C₃alkyl, or halo; or R¹ and R² are H.

In any of the above embodiments, R³ and R⁴ are, independently,carbocycle(R⁵)(R⁶), where R⁵ and R⁶ can be positioned anywhere on thecarbocycle. In any of the above embodiments, R³ and R⁴ are,independently,

wherein each W, Y, and Z are, independently, C or N, each A, D, and Qare, independently, C(R¹⁰)C(R¹¹), C(═O), N(R¹²), O, or S, and each R¹⁰,R¹¹, and R¹² are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,CF₃, or aromatic group.

In any of the above embodiments, R³ and R⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N; or R³ and R⁴ are,independently,

wherein each W, Y, and Z are C, or each Y and Z are C and each W is N.

In any of the above embodiments, each R⁵ is, independently, H,C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, or the free base or salt form of—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 8, and each R⁶ is, independently,heterocycle or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or each R⁵ is, independently, H, C₁-C₃alkyl,C₁-C₃alkoxy, halo, OH, or CF₃, and each R⁶ is, independently,heterocycle or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is, independently, 1 to 8; or each R⁵ is, independently, H,C₁-C₃alkyl, halo, or OH; and each R⁶ is, independently, heterocycle orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 4; or each R⁵ is, independently, H, C₁-C₃alkyl,halo, or OH; and each R⁶ is, independently, 6-membered heterocycle orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 3; or each R⁵ is, independently, H or halo; and eachR⁶ is piperazinyl or the free base or salt form of —(CH₂)_(n)—NH₂ whereeach n is, independently, 1 to 3; or each R⁵ is piperazinyl; and each R⁶is, independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, or CF₃; or eachR⁵ is piperazinyl; and each R⁶ is H, C₁-C₃alkyl, halo, OH, or CF₃.

In some embodiments, X is NH, O, S, or S(═O)₂; R¹ and R² are H; R³ andR⁴ are, independently,

wherein: each W, Y, and Z are, independently, C or N; each R⁵ and eachR⁶ are, independently, H, heterocycle, or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3.

In some embodiments, X is NH, O, or S; R¹ and R² are H; R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is, independently, H or halo, and each R⁶ is piperazinyl or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 3; or each R⁵ is piperazinyl, and each R⁶ is,independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, or CF₃.

In some embodiments, X is NH, O, or S; R¹ and R² are H; R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is H, and each R⁶ is piperazinyl or the free base or salt formof —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3; or each R⁵ ispiperazinyl; and each R⁶ is H.

In some embodiments, the compound is chosen from:

or pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present invention also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula I:

wherein:

X is C(R⁷)C(R⁸), C(═O), N(R⁹), O, S, S(═O), or S(═O)₂;

R⁷, R⁸, and R⁹ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,CF₃, or aromatic group;

R¹ and R² are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,haloC₁-C₈alkyl, or CN;

R³ and R⁴ are, independently, carbocycle(R⁵)(R⁶);

each R⁵ and each R⁶ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy,halo, OH, CF₃, aromatic group, heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is N(R⁹), O, S, or S(═O)₂; or X is NH, O, or S;or X is NH or S.

In any of the above embodiments, R¹ and R² are, independently, H,C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, haloC₁-C₃alkyl, or CN; or R¹ and R²are, independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, or OH; or R¹ andR² are, independently, H, C₁-C₃alkyl, or halo; or R¹ and R² are H.

In any of the above embodiments, R³ and R⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N, each A, D, and Qare, independently, C(R¹⁰)C(R¹¹), C(═O), N(R¹²), O, or S, and each R¹⁰,R¹¹, and R¹² are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,CF₃, or aromatic group.

In any of the above embodiments, R³ and R⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N; or R³ and R⁴ are,independently,

wherein each W, Y, and Z are C; or each Y and Z are C and each W is N.

In any of the above embodiments, each R⁵ is, independently, H,C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, or the free base or salt form of—(CH₂)_(n)—NH₂, (CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 8, and each R⁶ is, independently,heterocycle or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or each R⁵ is, independently, H, C₁-C₃alkyl,C₁-C₃alkoxy, halo, OH, or CF₃, and each R⁶ is, independently,heterocycle or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is, independently, 1 to 8; or each R⁵ is, independently, H,C₁-C₃alkyl, halo, or OH, and each R⁶ is, independently, heterocycle orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 4; or each R⁵ is, independently, H, C₁-C₃alkyl,halo, or OH, and each R⁶ is, independently, 6-membered heterocycle orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 3; or each R⁵ is, independently, H or halo, and eachR⁶ is piperazinyl or the free base or salt form of —(CH₂)_(n)—NH₂ whereeach n is, independently, 1 to 3; or each R⁵ is piperazinyl, and each R⁶is, independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, or CF₃; or eachR⁵ is piperazinyl, and each R⁶ is H, C₁-C₃alkyl, halo, OH, or CF₃.

In some embodiments, X is NH, O, S, or S(═O)₂; R¹ and R² are H; R³ andR⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N; and each R⁵ andeach R⁶ are, independently, H, heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3.

In some embodiments, X is NH, O, or S; R¹ and R² are H; R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is, independently, H or halo, and each R⁶ is piperazinyl or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 3; or each R⁵ is piperazinyl, and each R⁶ is,independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, or CF₃.

In some embodiments, X is NH, O, or S; R¹ and R² are H; R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is H, and each R⁶ is piperazinyl or the free base or salt formof —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3; or each R⁵ ispiperazinyl; and each R⁶ is H.

In some embodiments, the compound is chosen from:

or pharmaceutically acceptable salt thereof.

In any of the above embodiments, the malaria can bechloroquine-sensitive or chloroquine-resistant.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula I:

wherein:

X is C(R⁷)C(R⁸), C(═O), N(R⁹), O, S, S(═O), or S(═O)₂;

R⁷, R⁸, and R⁹ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,CF₃, or aromatic group;

R¹ and R² are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,haloC₁-C₈alkyl, or CN;

R³ and R⁴ are, independently, carbocycle(R⁵)(R⁶);

each R⁵ and each R⁶ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy,halo, OH, CF₃, aromatic group, heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is N(R⁹), O, S, or S(═O)₂; or X is NH, O, or S;or X is NH or S.

In any of the above embodiments, R¹ and R² are, independently, H,C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, haloC₁-C₃alkyl, or CN; or R¹ and R²are, independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, or OH; or R¹ andR² are, independently, H, C₁-C₃alkyl, or halo; or R¹ and R² are H.

In any of the above embodiments, R³ and R⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N, each A, D, and Qare, independently, C(R¹⁰)C(R¹¹), C(═O), N(R¹²), O, or S, and each R¹⁰,R¹¹, and R¹² are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH,CF₃, or aromatic group.

In any of the above embodiments, R³ and R⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N; or R³ and R⁴ are,independently,

wherein each W, Y, and Z are C; or each Y and Z are C and each W is N.

In any of the above embodiments, each R⁵ is, independently, H,C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, or the free base or salt form of—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 8, and each R⁶ is, independently,heterocycle or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or each R⁵ is, independently, H, C₁-C₃alkyl,C₁-C₃alkoxy, halo, OH, or CF₃, and each R⁶ is, independently,heterocycle or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is, independently, 1 to 8; or each R⁵ is, independently, H,C₁-C₃alkyl, halo, or OH, and each R⁶ is, independently, heterocycle orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 4; or each R⁵ is, independently, H, C₁-C₃alkyl,halo, or OH, and each R⁶ is, independently, 6-membered heterocycle orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 3; or each R⁵ is, independently, H or halo, and eachR⁶ is piperazinyl or the free base or salt form of —(CH₂)_(n)—NH₂ whereeach n is, independently, 1 to 3; or each R⁵ is piperazinyl, and each R⁶is, independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, or CF₃; or eachR⁵ is piperazinyl, and each R⁶ is H, C₁-C₃alkyl, halo, OH, or CF₃.

In some embodiments, X is NH, O, S, or S(═O)₂; R¹ and R² are H; R³ andR⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N; and each R⁵ andeach R⁶ are, independently, H, heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3.

In some embodiments, X is NH, O, or S; R¹ and R² are H; R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is, independently, H or halo, and each R⁶ is piperazinyl or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 3; or each R⁵ is piperazinyl, and each R⁶ is,independently, H, C₁-C₃alkyl, C₁-C₃alkoxy, halo, OH, or CF₃.

In some embodiments, X is NH, O, or S; R¹ and R² are H; R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is H, and each R⁶ is piperazinyl or the free base or salt formof —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3; or each R⁵ ispiperazinyl; and each R⁶ is H.

In some embodiments, the compound is chosen from:

or pharmaceutically acceptable salt thereof.

The present invention also provides compounds of Formula II:

wherein:

X is O or S;

each Y is, independently, O, S, or N;

each R¹ is, independently, H, 5- or 6-membered heterocycle, or the freebase or salt form of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4; or

each R¹ is, independently, together with Y a 5- or 6-memberedheterocycle;

each R² is, independently, H, CF₃, C(CH₃)₃, halo, or OH; and

each R³ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is O.

In any of the above embodiments, each Y is O or S.

In any of the above embodiments, each R¹ is, independently, 5-memberedheterocycle or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is, independently, 1 to 4; or each R¹ is, independently, 3-pyrrolyl orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 or 2.

In any of the above embodiments, each R² is, independently, CF₃,C(CH₃)₃, or halo.

In any of the above embodiments, each R³ is, independently,(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachR³ is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, X is O or S; each Y is, independently, O or S; eachR¹ is, independently, 5-membered heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4; each R²is, independently, CF₃ or C(CH₃)₃; and each R³ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, X is O or S; each Y is O or S; each R¹ is5-membered heterocycle, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 1 to 4; each R² is CF₃ or C(CH₃)₃; and each R³ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, X is O or S; each Y is O or S; each R¹ is3-pyrrolyl, or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is 2; each R² is CF₃ or C(CH₃)₃; and each R³ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present invention also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula II:

wherein:

X is O or S;

each Y is, independently, O, S, or N;

each R¹ is, independently, H, 5- or 6-membered heterocycle, or the freebase or salt form of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4; or

each R¹ is, independently, together with Y a 5- or 6-memberedheterocycle;

each R² is, independently, H, CF₃, C(CH₃)₃, halo, or OH; and

each R³ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is O.

In any of the above embodiments, each Y is O or S.

In any of the above embodiments, each R¹ is, independently, 5-memberedheterocycle or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is, independently, 1 to 4; or each R¹ is, independently, 3-pyrrolyl orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 or 2.

In any of the above embodiments, each R² is, independently, CF₃,C(CH₃)₃, or halo.

In any of the above embodiments, each R³ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachR³ is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, X is O or S; each Y is, independently, O or S; eachR¹ is, independently, 5-membered heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4; each R²is, independently, CF₃ or C(CH₃)₃; and each R³ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, X is O or S; each Y is O or S; each R¹ is5-membered heterocycle, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 1 to 4; each R² is CF₃ or C(CH₃)₃; and each R³ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, X is O or S; each Y is O or S; each R¹ is3-pyrrolyl, or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is 2; each R² is CF₃ or C(CH₃)₃; and each R³ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the malaria can bechloroquine-sensitive or chloroquine-resistant.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula II:

wherein:

X is O or S;

each Y is, independently, O, S, or N;

each R¹ is, independently, H, 5- or 6-membered heterocycle, or the freebase or salt form of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4; or each R¹ is, independently, togetherwith Y a 5- or 6-membered heterocycle;

each R² is, independently, H, CF₃, C(CH₃)₃, halo, or OH; and

each R³ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is O.

In any of the above embodiments, each Y is O or S.

In any of the above embodiments, each R¹ is, independently, 5-memberedheterocycle or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is, independently, 1 to 4; or each R¹ is, independently, 3-pyrrolyl orthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 or 2.

In any of the above embodiments, each R² is, independently, CF₃,C(CH₃)₃, or halo.

In any of the above embodiments, each R³ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachR³ is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, X is O or S; each Y is, independently, O or S; eachR¹ is, independently, 5-membered heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4; each R²is, independently, CF₃ or C(CH₃)₃; and each R³ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, X is O or S; each Y is O or S; each R¹ is5-membered heterocycle, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 1 to 4; each R² is CF₃ or C(CH₃)₃; and each R³ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, X is O or S; each Y is O or S; each R¹ is3-pyrrolyl, or the free base or salt form of —(CH₂)_(n)—NH₂, where eachn is 2; each R² is CF₃ or C(CH₃)₃; and each R³ is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present invention also provides compounds of Formula III:

Q-X—Z—X-Q

wherein:

Z is

or phenyl;

each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4;

each X is, independently, O, S, or N;

each R¹ is, independently, H, CF₃, C(CH₃)₃, halo, or OH;

each R³ is, independently, H, —NH—R², —(CH₂)_(r)—NH₂, —NH₂,—NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2;

each R² is, independently, H, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4;

each R⁴ is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and

each R⁵ is, independently, H or CF₃;

or a pharmaceutically acceptable salt thereof.

In some embodiments, Z is

In any of the above embodiments, each Q is, independently,

In any of the above embodiments, each X is O.

In any of the above embodiments, each R¹ is, independently, H, CF₃, orhalo; or

each R¹ is CF₃.

In any of the above embodiments, each R³ is, independently, —NH—R².

In any of the above embodiments, each R² is, independently, H, or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 4; or each R² is, independently, the free base orsalt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; oreach R² is the free base or salt form of —(CH₂)_(n)—NH₂, where each n is2.

In any of the above embodiments, each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is O or S; each R¹ is, independently, CF₃, C(CH₃)₃, or halo; eachR³ is, independently, —NH—R²; each R² is, independently, H, or the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 4; and each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is O; each R¹ is CF₃, C(CH₃)₃, or halo; each R³ is,independently, —NH—R²; each R² is, independently, the free base or saltform of —(CH₂)_(n)—NH₂, where each n is 1 or 2; and each R⁴ and each R⁵is H.

In some embodiments, Z is

each Q is, independently,

each X is O; each R¹ is CF₃ or halo; each R³ is, independently, —NH—R²;each R² is the free base or salt form of —(CH₂)_(n)—NH₂, where each n is2; and each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is, independently, O, or S; each R¹ is, independently, H, or CF₃;each R³ is H; each R⁴ is, independently, H or—NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂, where each p is, independently, 3 or4; and each R⁵ is, independently, H or CF₃.

In some embodiments, Z is

each Q is, independently, —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each bis, independently, 3 or 4; and each X is N.

In some embodiments, Z is

each Q is, independently,

each X is O or S; each R¹ is, independently, H or CF₃; each R³ is,independently, —(CH₂)_(r)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R⁴ is H; and each R⁵ is,independently, H or CF₃.

In some embodiments, Z is

or phenyl; each Q is, independently,

each X is, independently, O or S; each R¹ is, independently, H or CF₃;each R³ is H; each R⁴ is, independently,

where each q is, independently, 1 or 2; and each R⁵ is, independently, Hor CF₃.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present invention also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula III:

Q-X—Z—X-Q

wherein:

Z is

or phenyl;

each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4;

each X is, independently, O, S, or N;

each R¹ is, independently, H, CF₃, C(CH₃)₃, halo, or OH;

each R³ is, independently, H, —NH—R², —(CH₂)_(r)—NH₂, —NH₂,—NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2;

each R² is, independently, H, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4;

each R⁴ is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and

each R⁵ is, independently, H or CF₃;

or a pharmaceutically acceptable salt thereof.

In some embodiments, Z is

In any of the above embodiments, each Q is, independently,

In any of the above embodiments, each X is O.

In any of the above embodiments, each R¹ is, independently, H, CF₃, orhalo; or

each R¹ is CF₃.

In any of the above embodiments, each R³ is, independently, —NH—R².

In any of the above embodiments, each R² is, independently, H, or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 4; or each R² is, independently, the free base orsalt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; oreach R² is the free base or salt form of —(CH₂)_(n)—NH₂, where each n is2.

In any of the above embodiments, each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is O or S; each R¹ is, independently, CF₃, C(CH₃)₃, or halo; eachR³ is, independently, —NH—R²; each R² is, independently, H, or the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 4; and each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is O; each R¹ is CF₃, C(CH₃)₃, or halo; each R³ is,independently, —NH—R²; each R² is, independently, the free base or saltform of —(CH₂)_(n)—NH₂, where each n is 1 or 2; and each R⁴ and each R⁵is H.

In some embodiments, Z is

each Q is, independently,

each X is O; each R¹ is CF₃ or halo; each R³ is, independently, —NH—R²;each R² is the free base or salt form of —(CH₂)_(n)—NH₂, where each n is2; and each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is, independently, O, or S; each R¹ is, independently, H, or CF₃;each R³ is H; each R⁴ is, independently, H or—NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂, where each p is, independently, 3 or4; and each R⁵ is, independently, H or CF₃.

In some embodiments, Z is

each Q is, independently, —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each bis, independently, 3 or 4; and each X is N.

In some embodiments, Z is

each Q is, independently,

each X is O or S; each R¹ is, independently, H or CF₃; each R³ is,independently, —(CH₂)_(r)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R⁴ is H; and each R⁵ is,independently, H or CF₃.

In some embodiments, Z is

or phenyl; each Q is, independently,

each X is, independently, O or S; each R¹ is, independently, H or CF₃;each R³ is H; each R⁴ is, independently,

where each q is, independently, 1 or 2; and each R⁵ is, independently, Hor CF₃.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the malaria can bechloroquine-sensitive or chloroquine-resistant.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula III:

Q-X—Z—X-Q

wherein:

Z is

or phenyl;

each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4;

each X is, independently, O, S, or N;

each R¹ is, independently, H, CF₃, C(CH₃)₃, halo, or OH;

each R³ is, independently, H, —NH—R², —(CH₂)_(r)—NH₂, —NH₂,—NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2;

each R² is, independently, H, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4;

each R⁴ is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and

each R⁵ is, independently, H or CF₃;

or a pharmaceutically acceptable salt thereof.

In some embodiments, Z is

In any of the above embodiments, each Q is, independently,

In any of the above embodiments, each X is O.

In any of the above embodiments, each R¹ is, independently, H, CF₃, orhalo; or each R¹ is CF₃.

In any of the above embodiments, each R³ is, independently, —NH—R².

In any of the above embodiments, each R² is, independently, H, or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 4; or each R² is, independently, the free base orsalt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; oreach R² is the free base or salt form of —(CH₂)_(n)—NH₂, where each n is2.

In any of the above embodiments, each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is O or S; each R¹ is, independently, CF₃, C(CH₃)₃, or halo; eachR³ is, independently, —NH—R²; each R² is, independently, H, or the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 4; and each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is O; each R¹ is CF₃, C(CH₃)₃, or halo; each R³ is,independently, —NH—R²; each R² is, independently, the free base or saltform of —(CH₂)_(n)—NH₂, where each n is 1 or 2; and each R⁴ and each R⁵is H.

In some embodiments, Z is

each Q is, independently,

each X is O; each R¹ is CF₃ or halo; each R³ is, independently, —NH—R²;each R² is the free base or salt form of —(CH₂)_(n)—NH₂, where each n is2; and each R⁴ and each R⁵ is H.

In some embodiments, Z is

each Q is, independently,

each X is, independently, O, or S; each R¹ is, independently, H, or CF₃;each R³ is H; each R⁴ is, independently, H or—NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂, where each p is, independently, 3 or4; and each R⁵ is, independently, H or CF₃.

In some embodiments, Z is

each Q is, independently, —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each bis, independently, 3 or 4; and each X is N.

In some embodiments, Z is

each Q is, independently,

each X is O or S; each R¹ is, independently, H or CF₃; each R³ is,independently, —(CH₂)_(r)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R⁴ is H; and each R⁵ is,independently, H or CF₃.

In some embodiments, Z is

or phenyl; each Q is, independently,

each X is, independently, O or S; each R¹ is, independently, H or CF₃;each R³ is H; each R⁴ is, independently,

where each q is, independently, 1 or 2; and each R⁵ is, independently, Hor CF₃.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present invention also provides compounds of Formula IV:

wherein:

G is

each X is, independently, O or S;

each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4;

each R² is, independently, H, C₁-C₈alkyl, or the free base or salt formof —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4;

each R³ is, independently, H, CF₃, C(CH₃)₃, halo, or OH; and

each R⁴ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, G is

and each X is S.

In any of the above embodiments, each R¹ is, independently, the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 4; or each R¹ is, independently, the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; or each R¹ isthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is 2.

In any of the above embodiments, each R² is, independently, C₁-C₃alkylor the free base or salt form of —(CH₂)_(n)—NH₂ where n is 1 to 4; oreach R² is, independently, C₁-C₃alkyl or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; or each R² is,independently, methyl or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is, independently, 2; or each R² is methyl or the free baseor salt form of —(CH₂)_(n)—NH₂, where each n is 2.

In any of the above embodiments, each R³ is, independently, CF₃,C(CH₃)₃, or halo; or each R³ is CF₃.

In any of the above embodiments, each R⁴ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachR⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, G is

each X is S; each R¹ is, independently, the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, C₁-C₈alkyl or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R³ is,independently, CF₃, C(CH₃)₃, or halo; and each R⁴ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 3 or 4.

In some embodiments, G is

each X is S; each R¹ is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 1 or 2; each R² is, independently, C₁-C₃alkyl or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is 2; each R³ is,independently, CF₃ or C(CH₃)₃; and each R⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 3 or 4.

In some embodiments, G is

each X is S; each R¹ is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 2; each R² is, independently, methyl or the free base orsalt form of —(CH₂)_(n)—NH₂, where each n is 2; each R³ is,independently, CF₃ or C(CH₃)₃; and each R⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 4.

In some embodiments, G is

each X is, independently, O or S; each R¹ is, independently, the freebase or salt form of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4; each R³ is, independently, H or CF₃;and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, G is

each X is, independently, O or S; each R¹ is

each R³ is, independently, H or CF₃; and each R⁴ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present invention also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula IV:

wherein:

G is

each X is, independently, O or S;

each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4;

each R² is, independently, H, C₁-C₈alkyl, or the free base or salt formof —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4;

each R³ is, independently, H, CF₃, C(CH₃)₃, halo, or OH; and

each R⁴ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, G is

and each X is S.

In any of the above embodiments, each R¹ is, independently, the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 4; or each R¹ is, independently, the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; or each R¹ isthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is 2.

In any of the above embodiments, each R² is, independently, C₁-C₃alkylor the free base or salt form of —(CH₂)_(n)—NH₂ where n is 1 to 4; oreach R² is, independently, C₁-C₃alkyl or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; or each R² is,independently, methyl or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is, independently, 2; or each R² is methyl or the free baseor salt form of —(CH₂)_(n)—NH₂, where each n is 2.

In any of the above embodiments, each R³ is, independently, CF₃,C(CH₃)₃, or halo; or each R³ is CF₃.

In any of the above embodiments, each R⁴ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachR⁴ is (CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, G is

each X is S; each R¹ is, independently, the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, C₁-C₈alkyl or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R³ is,independently, CF₃, C(CH₃)₃, or halo; and each R⁴ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 3 or 4.

In some embodiments, G is

each X is S; each R¹ is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 1 or 2; each R² is, independently, C₁-C₃alkyl or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is 2; each R³ is,independently, CF₃ or C(CH₃)₃; and each R⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 3 or 4.

In some embodiments, G is

each X is S; each R¹ is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 2; each R² is, independently, methyl or the free base orsalt form of —(CH₂)_(n)—NH₂, where each n is 2; each R³ is,independently, CF₃ or C(CH₃)₃; and each R⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 4.

In some embodiments, G is

each X is, independently, O or S; each R¹ is, independently, the freebase or salt form of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4; each R³ is, independently, H or CF₃;and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, G is

each X is, independently, O or S; each R¹ is

each R³ is, independently, H or CF₃; and each R⁴ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the malaria can bechloroquine-sensitive or chloroquine-resistant.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula IV:

wherein:

G is

each X is, independently, O or S;

each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4;

each R² is, independently, H, C₁-C₈alkyl, or the free base or salt formof —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4;

each R³ is, independently, H, CF₃, C(CH₃)₃, halo, or OH; and

each R⁴ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, G is

and each X is S.

In any of the above embodiments, each R¹ is, independently, the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 4; or each R¹ is, independently, the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; or each R¹ isthe free base or salt form of —(CH₂)_(n)—NH₂, where each n is 2.

In any of the above embodiments, each R² is, independently, C₁-C₃alkylor the free base or salt form of —(CH₂)_(n)—NH₂ where n is 1 to 4; oreach R² is, independently, C₁-C₃alkyl or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; or each R² is,independently, methyl or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is, independently, 2; or each R² is methyl or the free baseor salt form of —(CH₂)_(n)—NH₂, where each n is 2.

In any of the above embodiments, each R³ is, independently, CF₃,C(CH₃)₃, or halo; or each R³ is CF₃.

In any of the above embodiments, each R⁴ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachR⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, G is

each X is S; each R¹ is, independently, the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, C₁-C₈alkyl or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R³ is,independently, CF₃, C(CH₃)₃, or halo; and each R⁴ is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 3 or 4.

In some embodiments, G is

each X is S; each R¹ is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 1 or 2; each R² is, independently, C₁-C₃alkyl or thefree base or salt form of —(CH₂)_(n)—NH₂, where each n is 2; each R³ is,independently, CF₃ or C(CH₃)₃; and each R⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 3 or 4.

In some embodiments, G is

each X is S; each R¹ is the free base or salt form of —(CH₂)_(n)—NH₂,where each n is 2; each R² is, independently, methyl or the free base orsalt form of —(CH₂)_(n)—NH₂, where each n is 2; each R³ is,independently, CF₃ or C(CH₃)₃; and each R⁴ is —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 4.

In some embodiments, G is

each X is, independently, O or S; each R¹ is, independently, the freebase or salt form of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4; each R³ is, independently, H or CF₃;and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, G is

each X is, independently, O or S; each R¹ is

each R³ is, independently, H or CF₃; and each R⁴ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present invention also provides compounds of Formula V:

wherein:

each X is, independently, O, S, or S(═O)₂;

each R¹ is, independently, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is,independently, 1 or 2;

each R² is, independently, H, halo, CF₃, or C(CH₃)₃; and

each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where eachn is, independently, 1 to 4; or each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof,

provided that the compound is not:

a)

b)

orc)

In some embodiments, each X is S.

In any of the above embodiments, each R¹ is, independently,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 or 2, and each R⁴ is, independently, Hor methyl; or each R¹ is, independently, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴, where each n is 2and each R⁴ is H; or each R¹ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or each R¹ is —(CH₂)_(n)—NH₂or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2.

In any of the above embodiments, each R² is, independently, H, Br, F,Cl, CF₃, or C(CH₃)₃; or each R² is Br, F, Cl, CF₃, or C(CH₃)₃.

In any of the above embodiments, each V² is H and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each V² is H and each V¹ is, independently,—N—C(═O)—R³, where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 or 2; or eachV² is H and each V¹ is, independently, N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 2; or each V² is H and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where n is 2.

In any of the above embodiments, each V¹ is H and each V² is,independently, —S—R⁵ where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 1 or 2; or each V¹ is H and each V² is, independently, —S—R⁵, whereeach R⁵ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 2; or each V¹ is H and each V² is —S—R⁵ where each R⁵ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂ where each n is 2.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, CF₃, or C(CH₃)₃;and each V¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, CF₃ or C(CH₃)₃; and each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂,where each n is, independently, 1 or 2.

In some embodiments, each X is S; each R¹ is —(CH₂)_(n)—NH₂, where eachn is 1 or 2; each R² is, independently, CF₃ or C(CH₃)₃; and each V¹ is Hand each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂, where each n is 1or 2.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴where each n is, independently, 1 to 4, and each R⁴ is, independently, Hor methyl; each R² is, independently, halo, CF₃, or C(CH₃)₃; and each V²is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 or 2, and eachR⁴ is, independently, H or methyl; each R² is, independently, halo; andeach V² is H, and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or (CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, CF₃, or C(CH₃)₃;and each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where eachR³ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4.

In some embodiments, each X is O or S; each R¹ is —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2; each R² is halo, CF₃,or C(CH₃)₃; and each V² is H, and each V¹ is —N—C(═O)—R³, where each R³is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 3 or 4.

In some embodiments, each X is, independently, S or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═O)—R⁴, where each nis, independently, 1 or 2, and each R⁴ is, independently,—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2; each R² is,independently, halo or CF₃; and each V² is H, and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present invention also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula V:

wherein:

each X is, independently, O, S, or S(═O)₂;

each R¹ is, independently, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is,independently, 1 or 2;

each R² is, independently, H, halo, CF₃, or C(CH₃)₃; and

each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where eachn is, independently, 1 to 4; or each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each X is S.

In any of the above embodiments, each R¹ is, independently,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴ whereeach n is, independently, 1 or 2, and each R⁴ is, independently, H ormethyl; or each R¹ is, independently, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴ where each n is 2 andeach R⁴ is H; or each R¹ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or each R¹ is —(CH₂)_(n)—NH₂or, where each n is 2.

In any of the above embodiments, each R² is, independently, H, Br, F,Cl, CF₃, or C(CH₃)₃; or each R² is Br, F, Cl, CF₃, or C(CH₃)₃.

In any of the above embodiments, each V² is H and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each V² is H and each V¹ is, independently,—N—C(═O)—R³, where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 or 2; or eachV² is H and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 2; or each V² is H and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where n is 2.

In any of the above embodiments, each V¹ is H and each V² is,independently, —S—R⁵ where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂ where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵⁵ where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 1 or 2; or each V¹ is H and each V² is, independently, —S—R⁵⁵ whereeach R⁵ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 2; or each V¹ is H and each V² is —S—R⁵ where each R⁵ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂ where each n is 2.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, CF₃, or C(CH₃)₃;and each V¹ is H and each V² is, independently, —S—R⁵⁵ where each R⁵ is,independently, —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, CF₃ or C(CH₃)₃; and each V¹ is H and each V² is,independently, —S—R⁵⁵ where each R⁵ is, independently, —(CH₂)_(n)—NH₂,where each n is, independently, 1 or 2.

In some embodiments, each X is S; each R¹ is —(CH₂)_(n)—NH₂, where eachn is 1 or 2; each R² is, independently, CF₃ or C(CH₃)₃; and each V¹ is Hand each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂, where each n is 1or 2.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 to 4, and each R⁴ is, independently, Hor methyl; each R² is, independently, halo, CF₃, or C(CH₃)₃; and each V²is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 or 2, and eachR⁴ is, independently, H or methyl; each R² is, independently, halo; andeach V² is H, and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, CF₃, or C(CH₃)₃;and each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where eachR³ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4.

In some embodiments, each X is O or S; each R¹ is —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2; each R² is halo, CF₃,or C(CH₃)₃; and each V² is H, and each V¹ is —N—C(═O)—R³, where each R³is —(CH₂)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 3 or 4.

In some embodiments, each X is, independently, S or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═O)—R⁴, where each nis, independently, 1 or 2, and each R⁴ is, independently,—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2; each R² is,independently, halo or CF₃; and each V² is H, and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the malaria can bechloroquine-sensitive or chloroquine-resistant.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula V:

wherein:

each X is, independently, O, S, or S(═O)₂;

each R¹ is, independently, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is,independently, 1 or 2;

each R² is, independently, H, halo, CF₃, or C(CH₃)₃; and

each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where eachn is, independently, 1 to 4; or each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each X is S.

In any of the above embodiments, each R¹ is, independently,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴ whereeach n is, independently, 1 or 2, and each R⁴ is, independently, H ormethyl; or each R¹ is, independently, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴ where each n is 2 andeach R⁴ is H; or each R¹ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or each R¹ is —(CH₂)_(n)—NH₂or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2.

In any of the above embodiments, each R² is, independently, H, Br, F,Cl, CF₃, or C(CH₃)₃; or each R² is Br, F, Cl, CF₃, or C(CH₃)₃.

In any of the above embodiments, each V² is H and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each V² is H and each V¹ is, independently,—N—C(═O)—R³, where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 or 2; or eachV² is H and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 2; or each V² is H and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where n is 2.

In any of the above embodiments, each V¹ is H and each V² is,independently, —S—R⁵ where each R⁵ is, independently, —(CH₂)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 1 or 2; or each V¹ is H and each V² is, independently, —S—R⁵, whereeach R⁵ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 2; or each V¹ is H and each V² is —S—R⁵ where each R⁵ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂ where each n is 2.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, CF₃, or C(CH₃)₃;and each V¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, CF₃ or C(CH₃)₃; and each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂,where each n is, independently, 1 or 2.

In some embodiments, each X is S; each R¹ is —(CH₂)_(n)—NH₂, where eachn is 1 or 2; each R² is, independently, CF₃ or C(CH₃)₃; and each V¹ is Hand each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂, where each n is 1or 2.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 to 4, and each R⁴ is, independently, Hor methyl; each R² is, independently, halo, CF₃, or C(CH₃)₃; and each V²is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 or 2, and eachR⁴ is, independently, H or methyl; each R² is, independently, halo; andeach V² is H, and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, CF₃, or C(CH₃)₃;and each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where eachR³ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, whereeach n is, independently, 1 to 4.

In some embodiments, each X is O or S; each R¹ is —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2; each R² is halo, CF₃,or C(CH₃)₃; and each V² is H, and each V¹ is —N—C(═O)—R³, where each R³is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 3 or 4.

In some embodiments, each X is, independently, S or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═O)—R⁴, where each nis, independently, 1 or 2, and each R⁴ is, independently,—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2; each R² is,independently, halo or CF₃; and each V² is H, and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present invention also provides compounds of Formula VI:

wherein:

each Y is, independently, O, S, or NH;

each R¹ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4; and

each R² is, independently, H, halo, CF₃, or C(CH₃)₃;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each Y is, independently, O, or S; or each Y is Oor S.

In any of the above embodiments, each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 2 to 4; or each R¹ is—(CH₂)_(n)—NH₂, where each n is 2 to 4.

In any of the above embodiments, each R² is, independently, halo, CF₃,or C(CH₃)₃; or each R² is halo, CF₃, or C(CH₃)₃.

In some embodiments, the compound is

or pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present invention also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula VI:

wherein:

each Y is, independently, O, S, or NH;

each R¹ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4; and

each R² is, independently, H, halo, CF₃, or C(CH₃)₃;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each Y is, independently, O, or S; or each Y is Oor S.

In any of the above embodiments, each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 2 to 4; or each R¹ is—(CH₂)_(n)—NH₂, where each n is 2 to 4.

In any of the above embodiments, each R² is, independently, halo, CF₃,or C(CH₃)₃; or each R² is halo, CF₃, or C(CH₃)₃.

In some embodiments, the compound is

or pharmaceutically acceptable salt thereof.

In any of the above embodiments, the malaria can bechloroquine-sensitive or chloroquine-resistant.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula VI:

wherein:

each Y is, independently, O, S, or NH;

each R¹ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4; and

each R² is, independently, H, halo, CF₃, or C(CH₃)₃;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each Y is, independently, O, or S; or each Y is Oor S.

In any of the above embodiments, each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 2 to 4; or each R¹ is—(CH₂)_(n)—NH₂, where each n is 2 to 4.

In any of the above embodiments, each R² is, independently, halo, CF₃,or C(CH₃)₃; or each R² is halo, CF₃, or C(CH₃)₃.

In some embodiments, the compound is

or pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula VII:

wherein:

each R¹ is, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, orCN;

each R² is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹ is, independently, C₁-C₈alkyl, halo, OH,CF₃, or CN; or each R¹ is, independently, C₁-C₃alkyl, halo, CF₃, or CN;or each R¹ is methyl or halo; or each R¹ is Br, F, or Cl.

In any of the above embodiments, each R² is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachR² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4; or each R² is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2.

In some embodiments, each R¹ is, independently, C₁-C₈alkyl, halo, OH,CF₃, or CN; and each R² is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4.

In some embodiments, each R¹ is, independently, C₁-C₃alkyl, halo, CF₃,or CN; and each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, each R¹ is methyl or halo; and each R² is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, the malaria can bechloroquine-sensitive or chloroquine-resistant.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula VII:

wherein:

each R¹ is, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, orCN;

each R² is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹ is, independently, C₁-C₈alkyl, halo, OH,CF₃, or CN; or each R¹ is, independently, C₁-C₃alkyl, halo, CF₃, or CN;or each R¹ is methyl or halo; or each R¹ is Br, F, or Cl.

In any of the above embodiments, each R² is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachR² is (CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4; or each R² is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2.

In some embodiments, each R¹ is, independently, C₁-C₈alkyl, halo, OH,CF₃, or CN; and each R² is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4.

In some embodiments, each R¹ is, independently, C₁-C₃alkyl, halo, CF₃,or CN; and each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, each R¹ is methyl or halo; and each R² is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

The present invention also provides compounds of Formula VIII:

wherein:

D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and

each X is, independently, O or S;

or a pharmaceutically acceptable salt thereof.

In some embodiments, D is

In any of the above embodiments, each B is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In any of the above embodiments, each X is S.

In some embodiments, D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4, or

and each X is S.

In some embodiments, D is

each B is, independently,

and each X is, independently, O or S.

In some embodiments, the compound is chosen from:

or pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present invention also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present invention also provides methods of treating malaria in ananimal comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula VIII:

wherein:

D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and

each X is, independently, O or S;

or a pharmaceutically acceptable salt thereof.

In some embodiments, D is

In any of the above embodiments, each B is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In any of the above embodiments, each X is S.

In some embodiments, D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4, or

and each X is S.

In some embodiments, D is

each B is, independently,

and each X is, independently, O or S.

In some embodiments, the compound is chosen from:

or pharmaceutically acceptable salt thereof.

In any of the above embodiments, the malaria can bechloroquine-sensitive or chloroquine-resistant.

The present invention also provides methods of killing or inhibiting thegrowth of a Plasmodium species comprising contacting the species with aneffective amount of a compound of Formula VIII:

wherein:

D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and

each X is, independently, O or S;

or a pharmaceutically acceptable salt thereof.

In some embodiments, D is

In any of the above embodiments, each B is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In any of the above embodiments, each X is S.

In some embodiments, D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4, or

and each X is S.

In some embodiments, D is

each B is, independently,

and each X is, independently, O or S.

In some embodiments, the compound is chosen from:

or pharmaceutically acceptable salt thereof.

It is to be understood that within any particular Formula, any oneembodiment can be combined with any other embodiment(s), as deemedappropriate.

In some embodiments, the anti-malarial compound(s) can be chosen fromone or more of the compounds (i.e., genuses, sub-genuses, and species)disclosed in U.S. Patent Application Publication Nos. US 2005/0287108and/or US 2006/0041023, each of which is incorporated herein byreference in its entirety. The methods described herein can also becarried out using any one or more of the compounds disclosed as a genus,sub-genus, or species of U.S. Patent Application Publication Nos. US2005/0287108 and/or US 2006/0041023.

Some of the compounds of the present invention may be capable ofadopting amphiphilic conformations that allow for the segregation ofpolar and nonpolar regions of the molecule into different spatialregions and provide the basis for a number of uses. For example, someanti-malarial compounds may adopt amphiphilic conformations that arecapable of disrupting the integrity of the cell membrane ofmicroorganisms, resulting in the inhibition of growth or the death of,for example, Plasmodium species.

The anti-malarial compounds can be useful as anti-malarial agents in anumber of applications. For example, anti-malarial compounds can be usedtherapeutically to treat malaria in animals, including humans andnon-human vertebrates such as wild, domestic and farm animals. Themalarial infection in an animal can be treated by administering to theanimal an effective amount of an anti-malarial compound, or apharmaceutical composition comprising the same. The anti-malarialcompound, or composition thereof, can be administered systemically ortopically and can be administered to any body site or tissue.

Although the anti-malarial compounds are suitable, other functionalgroups can be incorporated into the compound with an expectation ofsimilar results. In particular, thioamides and thioesters areanticipated to have very similar properties. The distance betweenaromatic rings can impact the geometrical pattern of the compound andthis distance can be altered by incorporating aliphatic chains ofvarying length, which can be optionally substituted or can comprise anamino acid, a dicarboxylic acid or a diamine. The distance between andthe relative orientation of monomers within the compounds can also bealtered by replacing the amide bond with a surrogate having additionalatoms. Thus, replacing a carbonyl group with a dicarbonyl alters thedistance between the monomers and the propensity of dicarbonyl unit toadopt an anti arrangement of the two carbonyl moiety and alter theperiodicity of the compound. Pyromellitic anhydride represents stillanother alternative to simple amide linkages which can alter theconformation and physical properties of the compound. Modern methods ofsolid phase organic chemistry (E. Atherton and R. C. Sheppard, SolidPhase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) nowallow the synthesis of homodisperse compounds with molecular weightsapproaching 5,000 Daltons. Other substitution patterns are equallyeffective.

The term “malarialcidal” as used herein means that the compoundinhibits, prevents, or destroys the growth or proliferation of aPlasmodium species.

The anti-malarial compounds can be incorporated into polishes, paints,sprays, or detergents formulated for application to surfaces to inhibitthe growth of a Plasmodium species thereon. These surfaces include, butare not limited to, surfaces such as, countertops, desks, chairs,laboratory benches, tables, floors, bed stands, tools or equipment,doorknobs, and windows. The anti-malarial compounds can also beincorporated into soaps and hand lotions. The present cleansers,polishes, paints, sprays, soaps, or detergents contain an anti-malarialcompound that provides a malarialstatic property to them. Theanti-malarial compounds can optionally contain suitable solvent(s),carrier(s), thickeners, pigments, fragrances, deodorizers, emulsifiers,surfactants, wetting agents, waxes, or oils. For example, in someaspects, the anti-malarial compounds can be incorporated into aformulation for external use as a pharmaceutically acceptable skincleanser, particularly for the surfaces of human hands. Cleansers,polishes, paints, sprays, soaps, hand lotions, and detergents and thelike containing the anti-malarial compounds can be useful in homes andinstitutions, particularly but not exclusively, in hospital settings forthe prevention of nosocomial infections.

In some aspects, the anti-malarial compounds include derivativesreferred to as prodrugs. The expression “prodrug” denotes a derivativeof a known direct acting drug, which derivative has enhanced deliverycharacteristics and therapeutic value as compared to the drug, and istransformed into the active drug by an enzymatic or chemical process.

It is understood that the present invention encompasses the use, whereapplicable, of stereoisomers, diastereomers and optical isomers of theanti-malarial compounds, as well as mixtures thereof, for treatingmalarial infections, an/or killing or inhibiting the growth of aPlasmodium species. Additionally, it is understood that stereoisomers,diastereomers, and optical isomers of the anti-malarial compounds, andmixtures thereof, are within the scope of the invention. By way ofnon-limiting example, the mixture may be a racemate or the mixture maycomprise unequal proportions of one particular stereoisomer over theother. Additionally, the anti-malarial compounds can be provided as asubstantially pure stereoisomers, diastereomers and optical isomers.

In another aspect, the anti-malarial compounds can be provided in theform of an acceptable salt (i.e., a pharmaceutically acceptable salt)for treating malarial infections, and/or killing or inhibiting thegrowth of a Plasmodium species. Salts can be provided for pharmaceuticaluse, or as an intermediate in preparing the pharmaceutically desiredform of the anti-malarial compounds. One salt that can be considered tobe acceptable is the hydrochloride acid addition salt. Hydrochlorideacid addition salts are often acceptable salts when the pharmaceuticallyactive agent has an amine group that can be protonated. Since ananti-malarial compound may be polyionic, such as a polyamine, theacceptable salt can be provided in the form of a poly(aminehydrochloride).

Polyamides and polyesters that are useful can be prepared by typicalcondensation polymerization and addition polymerization processes. See,for example, G. Odian, Principles of Polymerization, John Wiley & Sons,Third Edition (1991), M. Steven, Polymer Chemistry, Oxford UniversityPress (1999). Most commonly the polyamides are prepared by (a) thermaldehydration of amine salts of carboxylic acids, (b) reaction of acidchlorides with amines and (c) aminolysis of esters. Methods (a) and (c)are of limited use in polymerizations of aniline derivatives which aregenerally prepared utilizing acid chlorides. The skilled chemist,however, will recognize that there are many alternative active acylatingagents, for example phosphoryl anhydrides, active esters or azides,which may replace an acid chloride and which, depending of theparticular polymer being prepared, may be superior to an acid chloride.The acid chloride route is probably the most versatile and baa been usedextensively for the synthesis of aromatic polyamides.

Homopolymers derived from substituted aminobenzoic acid derivatives canalso prepared in a stepwise fashion. A stepwise process comprisescoupling an N-protected amino acid to an amine (or hydroxy group) andsubsequently removing the amine-protecting group and repeating theprocess. These techniques have been highly refined for synthesis ofspecific peptides, allow for the synthesis of specific sequences, andboth solid-phase and solution techniques for peptide synthesis aredirectly applicable to the present invention. An alternative embodimentof the present invention is the corresponding polysulfonamides that canbe prepared in analogous fashion by substituting sulfonyl chlorides forcarboxylic acid chlorides.

The most common method for the preparation of polyureas is the reactionof diamines with diisocyanates (Yamaguchi, et al., Polym. Bull., 2000,44, 247). This exothermic reaction can be carried out by solutiontechniques or by interfacial techniques. One skilled in organic andpolymer chemistry will appreciate that the diisocyanate can be replacedwith a variety of other bis-acylating agents e.g., phosgene orN,N′-(diimidazolyl)carbonyl, with similar results. Polyurethanes areprepared by comparable techniques using a diisocyanate and a dialcoholor by reaction of a diamine with a bis-chloroformate.

The syntheses of the anti-malarial compounds can be carried out byroutine and/or known methods such as those disclosed in, for example,U.S. Patent Application Publication Nos. US 2005/0287108 and US2006/0041023, each of which is incorporated herein by reference in itsentirety. Numerous pathways are available to incorporate polar andnonpolar side chains. Phenolic groups on the monomer can be alkylated.Alkylation of the commercially available phenol will be accomplishedwith standard Williamson ether synthesis for the non-polar side chainwith ethyl bromide as the alkylating agent. Polar sidechains can beintroduced with bifunctional alkylating agents such as BOC-NH(CH₂)₂Br.Alternatively, the phenol group can be alkylated to install the desiredpolar side chain function by employing the Mitsonobu reaction withBOC-NH(CH₂)₂—OH, triphenyl phosphine, and diethylacetylenedicarboxylate. Standard conditions for reduction of the nitrogroups and hydrolysis of the ester afford the amino acid. With theaniline and benzoic acid in hand, coupling can be effected under avariety of conditions. Alternatively, the hydroxy group of the(di)nitrophenol can be converted to a leaving group and a functionalityintroduced under nucleophilic aromatic substitution conditions. Otherpotential scaffolds that can be prepared with similar sequences aremethyl 2-nitro-4-hydroxybenzoate and methyl 2-hydroxy-4-nitrobenzoate.

The anti-malarial compounds can also be designed using computer-aidedcomputational techniques, such as de novo design techniques, to embodythe amphiphilic properties. In general, de novo design of anti-malarialcompounds is performed by defining a three-dimensional framework of thebackbone assembled from a repeating sequence of monomers using moleculardynamics and quantum force field calculations. Next, side groups arecomputationally grafted onto the backbone to maximize diversity andmaintain drug-like properties. The best combinations of functionalgroups are then computationally selected to produce a cationic,amphiphilic structures. Representative compounds can be synthesized fromthis selected library to verify structures and test their biologicalactivity. Novel molecular dynamic and coarse grain modeling programshave also been developed for this approach because existing force fieldsdeveloped for biological molecules, such as peptides, were unreliable inthese oligomer applications (Car, R., and Parrinello, M., Phys. Rev.Lett., 55:2471-2474 (1985); Siepmann, J. I., and Frenkel, D., Mol. Phys.75:59-70 (1992); Martin, M. G., and Siepmann, J. I., J. Phys. Chem. B103:4508-4517 (1999); Brooks, B. R., et al., J. Comp. Chem. 4:187-217(1983)). Several chemical structural series of compounds have beenprepared. See, for example, WO 02/100295 A2, which is incorporatedherein by reference in its entirety. The anti-malarial compounds can beprepared in a similar manner. Molecular dynamic and coarse grainmodeling programs can be used for a design approach. See, for example,U.S. Patent Application No. US 2004-0107056, and U.S. Patent ApplicationNo. US 2004-0102941, each of which is incorporated herein by referencein its entirety.

After verifying the suitability of the force field by comparing computedpredictions of the structure and thermodynamic properties to moleculesthat have similar torsional patterns and for which experimental data areavailable, the fitted torsions can then be combined with bondstretching, bending, one-four, van der Waals, and electrostaticpotentials borrowed from the CHARMM (Brooks, B. R., et al., J. Comp.Chem. 4:187-217 (1983)) and TraPPE (Martin, M. G., and Siepmann, J. I.,J. Phys. Chem. B 103:4508-4517 (1999); Wick, C. D., et al., J. Phys.Chem. B 104:3093-3104 (2000)) molecular dynamics force fields. Toidentify conformations that can adopt periodic folding patterns withpolar groups and apolar groups lined up on the opposite sides, initialstructures can be obtained with the Gaussian package (Frisch, M., etal., Gaussian 98 (revision A.7) Gaussian Inc., Pittsburgh, Pa. 1998).Then, the parallelized plane-wave Car-Parrinello CP-MD (Car, R., andParrinello, M., Phys. Rev. Lett. 55:2471-2474 (1985)) program, (cf.Rothlisberger, U., et al., J. Chem. Phys. 3692-3700 (1996)) can be usedto obtain energies at the minimum and constrained geometries. Theconformations of the compounds without side-chains can be investigatedin the gas phase. Both MD and MC methods can be used to sample theconformations. The former is useful for global motions of the compound.With biasing techniques (Siepmann, J. I., and Frenkel, D., Mol. Phys.75:59-70 (1992); Martin, M. G., and Siepmann, J. I., J. Phys. Chem. B103:4508-4517 (1999); Vlugt, T. J. H., et al. Mol. Phys. 94:727-733(1998)), the latter allows efficient sampling for compounds withmultiple local minimum configurations that are separated by relativelylarge barriers.

The potential conformations are examined for positions to attach pendantgroups that will impart amphiphilic character to the secondarystructure. Compounds selected from the gas phase studies with suitablebackbone conformations and with side-chains at the optimal positions tointroduce amphiphilicity can be further evaluated in a model interfacialsystem. n-hexane/water can be chosen because it is simple and cheap forcalculations while it mimics well the lipid/water bilayer environment.Compound secondary structures that require inter-compound interactionscan be identified by repeating the above-mentioned calculations using aperiodically repeated series of unit cells of various symmetries (socalled variable cell molecular dynamics or Monte Carlo technique) withor without solvent. The results of these calculations can guide theselection of candidates for synthesis.

An example of the design, synthesis, and testing of arylamide polymersand oligomers, a related group of compounds of the invention, ispresented in Tew, G. N., et al., Proc. Natl. Acad. Sci. USA 99:5110-5114(2002), which is incorporated herein by reference in its entirety.

The anti-malarial compounds can be synthesized by solid-phase syntheticprocedures well know to those of skill in the art. See, for example, Tewet al. (Tew, G. N., et al., Proc. Natl. Acad. Sci. USA 99:5110-5114(2002)). See also Barany, G., et al., Int. J. Pept. Prot. Res.30:705-739 (1987); Solid-phase Synthesis: A Practical Guide, Kates, S.A., and Albericio, F., eds., Marcel Dekker, New York (2000); andDörwald, F. Z., Organic Synthesis on Solid Phase: Supports, Linkers,Reactions, 2nd Ed., Wiley-VCH, Weinheim (2002).

One of skill in the art will recognize that the anti-malarial compoundscan be tested for anti-malarial activity by methods well known to thoseof skill in the art. Any compound found to be active can be purified tohomogeneity and re-tested to obtain an accurate IC₅₀.

The anti-malarial compounds can be administered in any conventionalmanner by any route where they are active. Administration can besystemic, topical, or oral. For example, administration can be, but isnot limited to, parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, oral, buccal, or ocular routes, orintravaginally, by inhalation, by depot injections, or by implants.Thus, modes of administration for the anti-malarial compounds (eitheralone or in combination with other pharmaceuticals) can be, but are notlimited to, sublingual, injectable (including short-acting, depot,implant and pellet forms injected subcutaneously or intramuscularly), orby use of vaginal creams, suppositories, pessaries, vaginal rings,rectal suppositories, intrauterine devices, and transdermal forms suchas patches and creams. The selection of the specific route ofadministration and the dose regimen is to be adjusted or titrated by theclinician according to methods known to the clinician to obtain thedesired clinical response.

The amount of any particular anti-malarial compound to be administeredis that amount which is therapeutically effective. The dosage to beadministered will depend on the characteristics of the subject beingtreated, e.g., the particular animal treated, age, weight, health, typesof concurrent treatment, if any, and frequency of treatments, and can beeasily determined by one of skill in the art (e.g., by the clinician).The amount of an anti-malarial compound described herein that will beeffective in the treatment of malaria will depend on the nature of themalaria, and can be determined by standard clinical techniques. Inaddition, in vitro or in vivo assays may optionally be employed to helpidentify optimal dosage ranges. The precise dose to be employed in thecompositions will also depend on the route of administration, and theseriousness of the disorder, and should be decided according to thejudgment of the practitioner and each patient's circumstances. However,a suitable dosage range for oral administration is, generally, fromabout 0.001 milligram to about 200 milligrams per kilogram body weight.In some embodiments, the oral dose is from about 0.01 milligram to 100milligrams per kilogram body weight, from about 0.01 milligram to about70 milligrams per kilogram body weight, from about 0.1 milligram toabout 50 milligrams per kilogram body weight, from 0.5 milligram toabout 20 milligrams per kilogram body weight, or from about 1 milligramto about 10 milligrams per kilogram body weight. In some embodiments,the oral dose is about 5 milligrams per kilogram body weight.

The pharmaceutical compositions and/or formulations containing theanti-malarial compounds and a suitable carrier can be solid dosage formswhich include, but are not limited to, tablets, capsules, cachets,pellets, pills, powders and granules; topical dosage forms whichinclude, but are not limited to, solutions, powders, fluid emulsions,fluid suspensions, semi-solids, ointments, pastes, creams, gels andjellies, and foams; and parenteral dosage forms which include, but arenot limited to, solutions, suspensions, emulsions, and dry powder;comprising an effective amount of a anti-malarial compound. It is alsoknown in the art that the active ingredients can be contained in suchformulations with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,water soluble vehicles, emulsifiers, buffers, humectants, moisturizers,solubilizers, preservatives and the like. The means and methods foradministration are known in the art and an artisan can refer to variouspharmacologic references for guidance. For example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980) can be consulted.

The anti-malarial compounds can be formulated for parenteraladministration by injection, e.g., by bolus injection or continuousinfusion. The anti-malarial compounds can be administered by continuousinfusion subcutaneously over a period of about 15 minutes to about 24hours. Formulations for injection can be presented in unit dosage form,e.g., in ampoules or in multi-dose containers, with an addedpreservative. The compositions can take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing and/or dispersingagents.

For oral administration, the anti-malarial compounds can be formulatedreadily by combining these compounds with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the anti-malarialcompounds to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by, for example, adding a solid excipient,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include, but are notlimited to, fillers such as sugars, including, but not limited to,lactose, sucrose, mannitol, and sorbitol; cellulose preparations suchas, but not limited to, maize starch, wheat starch, rice starch, potatostarch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, andpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as, but not limited to, the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include, but arenot limited to, push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol. The push-fit capsules can contain the active ingredients inadmixture with filler such as, e.g., lactose, binders such as, e.g.,starches, and/or lubricants such as, e.g., talc or magnesium stearateand, optionally, stabilizers. In soft capsules, the active compounds canbe dissolved or suspended in suitable liquids, such as fatty oils,liquid paraffin, or liquid polyethylene glycols. In addition,stabilizers can be added. All formulations for oral administrationshould be in dosages suitable for such administration.

For buccal administration, the compositions can take the form of, e.g.,tablets or lozenges formulated in a conventional manner.

For administration by inhalation, the anti-malarial compounds for useaccording to the present invention are conveniently delivered in theform of an aerosol spray presentation from pressurized packs or anebulizer, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, e.g., gelatin for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The anti-malarial compounds can also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the anti-malarialcompounds can also be formulated as a depot preparation. Such longacting formulations can be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Depotinjections can be administered at about 1 to about 6 months or longerintervals. Thus, for example, the anti-malarial compounds can beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

In transdermal administration, the anti-malarial compounds can beapplied to a plaster, or can be applied by transdermal, therapeuticsystems that are consequently supplied to the organism.

The pharmaceutical compositions comprising the anti-malarial compoundsalso can comprise suitable solid or gel phase carriers or excipients.Examples of such carriers or excipients include, but are not limited to,calcium carbonate, calcium phosphate, various sugars, starches,cellulose derivatives, gelatin, and polymers such as, e.g., polyethyleneglycols.

In another embodiment, the anti-malarial compounds described herein canbe delivered in a vesicle, in particular a liposome (see, Langer,Science, 1990, 249, 1527-1533; Treat et al., in Liposomes in the Therapyof Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.),Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327;see generally ibid.).

In yet another embodiment, the anti-malarial compounds described hereincan be delivered in a controlled release system. In one embodiment, apump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed.Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507 Saudek etal., N. Engl. J. Med., 1989, 321, 574). In another embodiment, polymericmaterials can be used (see Medical Applications of Controlled Release,Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); ControlledDrug Bioavailability, Drug Product Design and Performance, Smolen andBall (eds.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci.Rev. Macromol. Chem., 1983, 23, 61; see, also Levy et al., Science,1985, 228, 190; During et al., Ann. Neurol., 1989, 25, 351; Howard etal., J. Neurosurg., 1989, 71, 105). In yet another embodiment, acontrolled-release system can be placed in proximity of the target ofthe anti-malarial compounds described herein, e.g., the liver, thusrequiring only a fraction of the systemic dose (see, e.g., Goodson, inMedical Applications of Controlled Release, supra, vol. 2, pp. 115-138(1984)). Other controlled-release systems discussed in the review byLanger, Science, 1990, 249, 1527-1533) may be used.

The anti-malarial compounds can also be administered in combination withother active ingredients such as, for example, antibiotics, including,but not limited to, vancomycin, ciprofloxacin, merapenem, oxicillin, andamikacin. The anti-malarial compounds can also be administered incombination with other anti-malarial compounds such as, for example, anyone or more of artemisinin, quinine, artesunate,sulfadoxine-pyrimethamine, hydroxychloroquine, chloroquine, amodiaquine,pyrimethamine, sulphadoxine, proguanil, mefloquine, atovaquone,primaquine, halofantrine, doxycycline, clindamycin.

Thus, the present invention also provides methods of treating malaria inan animal comprising administering to the animal in need thereof aneffective amount of an anti-malarial compound or a slat thereof. Thepresent invention also provides methods of treating malaria in an animalcomprising administering to the animal in need thereof a compositioncomprising an anti-malarial compound, or a slat thereof. The presentinvention also provides methods of killing or inhibiting the growth of aPlasmodium species comprising contacting the species with an effectiveamount of an anti-malarial compound, or salt thereof. The presentinvention also provides methods of killing or inhibiting the growth of aPlasmodium species comprising contacting the species with a compositioncomprising an anti-malarial compound, or salt thereof. The presentinvention also provides methods of killing or inhibiting the growth of achloroquine-sensitive or chloroquine-resistant Plasmodium speciescomprising contacting the species with an effective amount of ananti-malarial compound, or salt thereof. The present invention alsoprovides methods of killing or inhibiting the growth of achloroquine-sensitive or chloroquine-resistant Plasmodium speciescomprising contacting the species with a composition comprising ananti-malarial compound, or salt thereof. The present invention alsoprovides methods of disrupting a food vacuole of a Plasmodium speciescomprising contacting the species with an effective amount of ananti-malarial compound, or salt thereof. The present invention alsoprovides methods of disrupting a food vacuole of a Plasmodium speciescomprising contacting the species with a composition comprising ananti-malarial compound, or salt thereof.

An “animal in need thereof” is an animal that has been diagnosed withmalaria, an animal who is suspected of having malaria, and/or an animalthat is in an environment or will be traveling to an environment inwhich malaria is prevelant.

The present invention also provides anti-malarial compounds, or a saltthereof, or compositions comprising the same, for use in treating amalarial infection in an animal. The present invention also providesanti-malarial compounds, or a salt thereof, or compositions comprisingthe same, for use in killing or inhibiting the growth of a Plasmodiumspecies. The present invention also provides anti-malarial compounds, ora salt thereof, or compositions comprising the same, for use inpreparation of a medicament for treating a malarial infection in ananimal. The present invention also provides anti-malarial compounds, ora salt thereof, or compositions comprising the same, for use inpreparation of a medicament for killing or inhibiting the growth of aPlasmodium species.

The anti-malarial compounds described herein can be combined with one,two, or three other anti-malarial compounds described herein to form acocktail. This cocktail can also include other anti-malarial compounds.

In order that the invention disclosed herein may be more efficientlyunderstood, examples are provided below. It should be understood thatthese examples are for illustrative purposes only and are not to beconstrued as limiting the invention in any manner.

EXAMPLES Example 1 Synthesis of Compounds 142 and 149

Step 1: The diamine (0.1 mmol) and({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)pentanoicacid (4 equivalence) were dissolved in 3 mL of pyridine and cooled to 0°C. The solution was added POCl₃ (4 equiv.) dropwise and stirred at 0° C.for 1.5 hours. The reaction was quenched with ice water. The solvent wasremoved on a rotovap.

Step 2: The product from step 1 was treated with 50% trifluoroaceticacid (TFA) in dichloromethane (DCM). The product was purified by reversephase chromatography.

Example 2 Synthesis of Compounds 109, 111, and 144

Step 1: 319.6 mg of 4,4-dihydroxyphenyl in 4.0 ml of dimethylformamide(DMF) were sequentially added to 839.0 mg of K₂CO₃, and 1.3166 g of3,5-dinitrobenzotrifluoride. The reaction mixture was heated to 125° C.with stirring for overnight. TLC analysis indicated the startingmaterial was consumed. The reaction was quenched with water andextracted with ethyl acetate (EtOAc) twice. The organic phase was washedwith water, brine and dried with sodium sulfate before beingconcentrated under reduced pressure. The product was purified by columnchromatography with a yield of 865.6 mg (69%).

Step 2: 312.3 mg of the product formed in step 1 in 5.0 ml of MeOH wassequentially added to 365.3 mg of NH₄Cl, and 400.2 mg of Zinc dust. Thereaction mixture was irradiated under microwave at 115° C. for 20minutes. LCMS analysis indicated the starting material was consumed. Thereaction mixture was filtered and concentrated. The residue was quenchedwith water and extracted with EtOAc twice. The organic phase was washedwith water, brine and dried with sodium sulfate before beingconcentrated under reduced pressure. The crude product was under highvacuum for 6 hours and was used without further purification.

Step 3: 44.9 mg of diamine formed in step 2 was added to(2-oxo-ethyl)-carbamic acid tert-butyl ester (2 equiv. for compounds 109and 111, 1 equiv. for compound 144) in 1.5 ml of anhydrous EtOH. Thereaction mixture was sequentially added 3 drops of HOAc and 78.6 mg ofNaCNBH₃. The reaction mixture was stirred at room temperature overnight.LCMS analysis indicated the starting material was consumed. The reactionmixture was concentrated and the residue was quenched with water andextracted with EtOAc twice. The organic phase was washed with water,brine and dried with sodium sulfate before being concentrated underreduced pressure. The product was purified by column chromatography witha yield of 72.3 mg (97%).

Step 4: 41.3 mg of Boc-protected diamine formed in step 3 in 1.5 ml ofDCM was added 1.5 ml of TFA and the reaction mixture was stirred at roomtemperature for 45 minutes. LCMS analysis indicated the startingmaterial was consumed. The reaction mixture was concentrated and theresidue was washed with ether twice. The white powder in 2 ml of etherwas further sonicated for 10 minutes. The white solid was then washedwith ether twice and was under high vacuum for 12 hours. The yield was39.6 mg.

Example 3 Synthesis of Compounds 148 and 147

Step 1: 1.1071 g ofbis-(4,4-dihydroxyphenyl)-bis-(trifluoromethyl)-methane in 4.0 ml of DMFwere sequentially added 1.36 g of K₂CO₃, and 1.2777 g of4-fluoro3-trifluoromethylbenzaldehyde. The reaction mixture was heatedto 130° C. and stirred for 6 hours. The reaction was quenched with waterand extracted with EtOAc twice. The organic phase was washed with water,brine and dried with sodium sulfate before was concentrated underreduced pressure. The product was purified by column chromatography witha yield of 400.0 mg.

Step 2: 71.4 mg of dialdehyde formed in step 1 in 3.0 ml ofdichloroethane was sequentially added 241.8 mg ofpiperazine-1-carboxylic acid tert-butyl ester, and 257.8 mg ofNaBH(OAc)₃. The reaction mixture was stirred at room temperatureovernight. LCMS analysis indicated the starting material was consumed.The reaction mixture was concentrated and the residue was quenched withNa₂CO₃ solution and extracted with EtOAc twice. The organic phase waswashed with water, brine and dried with sodium sulfate before beingconcentrated under reduced pressure. The product was purified by columnchromatography with a yield of 113.7 mg (91%).

Step 3: 73.0 mg of Boc-protected diamine formed in step 2 in 2.0 ml ofDCM was added 2.0 ml of TFA and the reaction mixture was stirred at roomtemperature for 45 minutes. LCMS analysis indicated the startingmaterial was consumed. The reaction mixture was concentrated and theresidue was washed with ether twice. The white powder in 2 ml of etherwas further sonicated for 10 minutes. The white solid was then washedwith ether twice and was under high vacuum for 12 hours. The yield was70.3 mg.

Example 4 Synthesis of Compounds 145 and 146

Compound 145 was synthesized using a similar procedure for compound 147.The starting materials for step 1 are4-[(4-hydroxyphenyl)sulfonyl]phenol and3-fluoro-4-trifluoromethylbenzaldehyde.

Compound 146 was synthesized using a similar procedure for compound 147.The starting materials for step 1 are4-[(4-hydroxyphenyl)sulfonyl]phenol and3-fluoro-5-trifluoromethylbenzaldehyde.

Example 5 Synthesis of Compound 143

Step 1: The starting material was made using the same procedure as step1 of the synthesis of compound 145. 60.6 mg of dialdehyde formed incoupling reaction in 2.0 ml of EtOH was sequentially added 220.3 mg ofNH₂OH.HCl, 0.5 ml of water, and 0.1 ml of pyridine. The reaction mixturewas irradiated under microwave at 120° C. for 30 minutes. LCMS analysisindicated the starting material was consumed. The reaction mixture wasconcentrated and the residue was quenched with 2 ml of water. The crudeproduct was filtered and used for the next step without furtherpurification.

Step 2: The crude product formed in step 1 above was dissolved in 4 mlof HOAc. Zn dust (321.3 mg) was added in two portions. The resultingmixture was heated at 60° C. for 6 hours. The reaction mixture wasfiltered and concentrated. The residue was charged with 5 ml oftetrahydrofuran (THF), 0.3 ml of triethylamine (TEA) and 100.6 mg of Bocanhydride. The reaction mixture was stirred at room temperature for 4hours and was quenched with Na₂CO₃ solution and extracted with EtOActwice. The organic phase was washed with water, brine and dried withsodium sulfate before being concentrated under reduced pressure. Theproduct was purified by column chromatography with a yield of 67.8 mg(82%, two steps).

Step 3: 42.1 mg of Boc-protected diamine formed in step 2 in 2.0 ml ofDCM was added 2.0 ml of TFA and the reaction mixture was stirred at roomtemperature for 45 minutes. LCMS analysis indicated the startingmaterial was consumed. The reaction mixture was concentrated and theresidue was washed with ether twice. The white powder in 2 ml of etherwas further sonicated for 10 minutes. The white solid was then washedwith ether twice and was under high vacuum for 12 hours. The yield was30.2 mg.

Example 6 Synthesis of Compounds 101, 102, 107, 113, 114, 121, 123, and124

Step 1: Dianiline (0.15 mol) and diacid (0.062 mol) were combined withpyridine (121 mL) and a stir bar in a nitrogen purged 2 L RBF andstirred to a suspension with small pieces for 15 minutes. Then EDCI(0.185 mol) was added and the mixture was stirred at ambient temperaturefor 7.5 hours. The reaction was quenched with water (810 mL). Theproduct was purified by column chromatography or trituation usingheptane and ethyl acetate.

Step 2: Product from step 1 (0.179 mol) and({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)pentanoicacid (0.734 mol) were dissolved in 2.1 L dry pyridine. The solution wascooled to −20° C. to 0° C. To the solution, POCl₃ (0.716 mol) was slowlyadded over 30 minutes. The reaction mixture was stirred for 2 hours at−20° C. to 0° C. and then it was allowed to warm to room temperature andstirred for another 2 hours. Ice water (8 L) was added to quench thereaction. The precipitated solid was collected and purified by eithercolumn chromatography or trituration.

Step 3: Product from step 3 (98.4 mmol) was dissolved in 465 mL offormic acid. The solution was added 246 mL of 4M HCl in dioxane andstirred at room temperature for 10 hours. To this reaction mixture wasadded 1-butanol (2.5 L). The resulting precipitate was collected byfiltration and purified by reverse phase column chromatography.

Example 7 Synthesis of Compounds 122 and 126-129

Step 1: The starting diamine is made using similar method as step 1 ofcommon synthesis 2. Diamine was treated with 50% Trifluoroacetic acid indichloromethane for 2 hours. The resulting solution was concentrated toan oil and triturated with cold diethyl ether. The solid was collectedby filtration.

Step 2: Product from step 1 (1 mmol) and N,N′-bis-Boc-1-guanylpyrazole(2 mmol) were dissolved in 10 mL of methanol followed by 2 equivalenceof mL of disopropylethylamine. The mixture was stirred overnight at roomtemperature before the solvent was removed by rotovap. The product waspurified by column chromatography.

Step 3: This step was carried out similar as step 2 of common synthesis2 using product from step 2 and N-tert-butoxycarbonylamino-pentanoicacid.

Step 4: This step is the same as step 3 in common synthesis 2.

Example 8 Synthesis of Compound 108

The synthesis is similar as common synthesis 2 except in step 3,({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)propanoicacid was used.

Example 9 Synthesis of Compound 125

Step 1 and 2 are similar to step 1 and 2 of the synthesis of compound101.

Step 3: Product from step 2 was treated with 20% piperidine in DMF.After diluted with ethyl acetate and washed with 10% citric acid andbrine, the organic phase was concentrated and triturated with hexane.

Step 4: Product from step 3 (0.03 mmol) was mixed with 4-nitrophenylformate (2 equiv.) in 3 mL of DMF, followed by the addition of DIEA (4equiv.). The reaction mixture was stirred for 4 hours before was dilutedwith ethyl acetate. The organic layer was washed with saturated K₂CO₃,10% citric acid and water before it was concentrated to a solid. Thesolid was treated with 50% TFA in DCM and purified by reverse phasecolumn chromatography.

Example 10 Synthesis of Compound 152

The starting material was made from step 1 to 2 in the synthesis ofcompound 123. The starting Boc-protected amide (0.023 mmol) and3-chloroperoxybenzoic acid (MCPBA, 42.3 mg) were dissolved in DCM (0.8mL) and stirred under Ar for 1 hour. The reaction mixture was dilutedwith DCM and washed with saturated Na₂S₂O₃, saturated NaHCO₃ and water.The organic layer was dried and concentrated to a solid. The solid wastreated with 50% TFA in DCM. The final product was purified by reversephase column chromatography.

Example 11 Synthesis of Compound 153

Step 1: Compound 124 (0.29 mmol) was dissolved in 10 mL of water andthen was added N-methyl morpholine (NMM, 2.7 equiv.) and 5 mL of DMF.N-Boc-Gly-Osu (2.2 mmol) in 5 mL DMF was added to the solution dropwise.The reaction mixture was stirred at room temperature for 20 minutesbefore it was concentrated to a solid.

Step 2: The product from step 1 was treated with 4 N HCl in dioxane andpurified with reverse phase column chromatography.

Example 12 Synthesis of Compounds 103-105 and 150

Step 1: Bisaniline and carbonyl diimidazole (CDI) were mixed in dry DMSO(with molar ratio bisaniline:CDI=4:1). The reaction mixture was stirredat 100° C. for 24 hours. After it cooled down, water was added toreaction mixture. The precipitate was filtered and dried under vacuum.The crude product was purified with silica gel column withdichloromethane and ethyl acetate as eluents.

Steps 2 and 3 are similar to steps 2 and 3 of the synthetic procedurefor compound 101.

Example 13 Synthesis of Compound 151

Step 1: Bisaniline (4 equiv.) and 1,4-benzenediisocyanate (1 equiv.)were mixed in dry DMSO. The reaction mixture was stirred at 100° C. for24 hours. After it cooled down, water was added to the reaction mixture.The precipitate was filtered and dried under vacuum. The crude productwas purified with silica gel column with dichloromethane and ethylacetate as eluents.

Steps 2 and 3 are similar to steps 2 and 3 of the synthetic procedurefor compound 101.

Example 14 Synthesis of Compound 112

2-Chloro-4,6-dimethoxy-1,3,5-triazine was stirred in anhydrous THF.N-Methylmorpholine was added. The resulting mixture was stirred at roomtemperature for 30 minutes. Then aniline and pyrimidine-4,6-dicarboxylicacid were added. The mixture was stirred at room temperature for 24hours. Then the solvent was evaporated completely in vacuum. Water wasadded and the mixture was stirred for 4 hours. The solid precipitate wascollected and purified by silica gel column with dichloromethane andethyl acetate as eluents. The Boc-protected compound was deprotectedusing 4N HCl dioxane solution overnight at room temperature to generatethe final product.

Example 15 Synthesis of Compounds 116 and 133-141

Compound 116 has been synthesized utilizing three synthetic schemes.

Step 1: 8-(dihydroxyboryl)dibenzo[b,d]thiophen-2-ylboronic acid (4 mmol,1.08 g) and 3-(3-bromophenyl)propanenitrile (8.8 mmol, 1.875 g) wereadded into a microwave tube under Argon. Dioxane (10 mL), Pd(PPh₃)₄ (0.4mmol, 0.46 g) and K₂CO₃ (16 mmol, 4 mL, 4M) were added. The mixture wasunder microwave irradiation (120° C., 15 minutes) with stirring. Thenthe reaction was cooled down to room temperature and extracted withEtOAc and brine. The organic layer was dried over NaSO₄ and evaporatedunder vacuum. The residue was purified with silica column (eluent:EtOAc/hexanes=1/2, v/v). A yellow solid (1.18 g, 70%) was obtained asproduct. ¹HNMR was acceptable.

Step 2: 2,8-di(3-phenylpropanenitrile)benzothiophene (1.33 mmol, 0.59 g)and platinum oxide hydrate (80 mg) were added into a mixture of MeOH (10mL)/EtOAC (40 mL). HCl (2 mol, 0.5 mL, 4M in dioxane) was added.Hydrogen at 60 psi was introduced after removal of air. The mixture wasshacked over night. Then the hydrogen was removed. The mixture wasfiltered through celite pad. The filtrate was evaporated under vacuum.The residue was purified by reverse phase HPLC. A white solid (70 mg,12%) was obtained as product. LC-MS and ¹HNMR were acceptable.

Step 1, 2 and 3: Synthesis of 2,8-di(tert-butyl 3-phenylpropylcarbamate)benzothiophene. The tert-butyl 3-(3-bromophenyl)propylcarbamateintermediate was synthesized from 3-(3-bromophenyl)propanenitrile by BH₃reduction and Boc protection. tert-Butyl3-(3-bromophenyl)propylcarbamate (2.2 mmol, 0.69 g), 8-(dihydroxyboryl)dibenzo[b,d]thiophen-2-ylboronic acid (1 mmol, 0.272 g) were added intoa microwave tube under Argon. Dioxane (4 mL), Pd(PPh₃)₄ (0.1 mmol, 0.115g) and K₂CO₃ (2 mmol, 2 mL, 4M) were added. The mixture was undermicrowave irradiation (120° C., 15 minutes) with stirring. Then thereaction was cooled down to room temperature and extracted with EtOAcand brine. The organic layer was dried over NaSO₄ and evaporated undervacuum. The residue was purified with silica column (eluent:EtOAc/hexanes=1/100-1/2, v/v). A yellow solid (1.0 g, 76.9%) wasobtained as product. ¹HNMR was acceptable.

Step 4: The yellow solid from above reaction was stirred in 10 ml HCl indioxane (4 M) at room temperature overnight. Then the mixture wasfiltrated and the cake was washed with ether. The solid was purified byreverse phase column. A white solid (0.376 g, 46.6%) was obtained. LC-MSand ¹HNMR were acceptable.

Intermediate 2,8-di(tert-butyl 3-phenylpropylcarbamate)benzothiophenewas synthesized by Suzuki reaction of 2,8-dibromodibenzothiophene andtert-butyl3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate,which was obtained from tert-butyl 3-(3-bromophenyl)propylcarbamate.Compound 116 was obtained following similar de-protection reactioncondition in route 2.

Compounds 133-141 can be prepared based upon the above synthesisschemes, as well as the synthesis schemes shown below, using routineexperimentation and knowledge of one skilled in the art.

Example 16 Synthesis of Compound 106

Following similar procedure in route 2 of compound 116, compound 106 wassynthesized in 45% overall yield as a white solid.

Example 17 Synthesis of Compounds 110, 117, 118, 119, 131, and 132

Following similar procedure in route 3 of compound 116, compounds 110,117, 118, 119, 131, and 132 were obtained in 68%, 40%, 20%, 22%, 71%,and 15% overall yield, respectively.

Example 18 Synthesis of Compound 130

Following similar procedure in route 1 of compound 116, compound 130 wasobtained in 7% overall yield.

Example 19 Synthesis of Compound 120

2,8-dibromodibenzo[b,d]furan was synthesized by bromination in 29%yield. Following similar procedure in route 3, compound 120 was obtainedin 69% after two-step reaction.

Example 20 Synthesis of Compounds 154-156

1.77 gram 2-Chloro-4,6-dimethoxy-1,3,5-triazine was stirred in anhydrous50 ml THF. 2.02 gram N-Methylmorpholine was added. The resulting mixturewas stirred at room temperature for 30 minutes. Then Bis-aniline andsalicylic acid were added. The mixture was stirred at room temperaturefor 24 hours. Then the solvent was evaporated completely in vacuum.Water was added and the mixture was stirred for 4 hours. The solidprecipitate was collected and dried in the vacuum. Then it was purifiedby crystallization with DCM and hexane. The Boc-protected compound wasdeprotected using 4N HCl dioxane solution overnight at room temperature.

Compounds 154 and 155 can be prepared based upon the above synthesisscheme, as well as the two synthesis schemes shown below, using routineexperimentation and knowledge of one skilled in the art.

Example 21 Synthesis of Compound 115

Compound 115 can be prepared based upon the synthesis scheme shownbelow, using routine experimentation and knowledge of one skilled in theart.

Recognizing the significant therapeutic limitations of peptides, aseries of non-peptidic mimics of these AMPs (SMAMPs) have been developedthat represent a novel and powerful therapy against many microbesincluding, for example, malaria. A number of small molecules,sequence-specific oligomers, and polymers SMAMPs have been designedherein that have robust in vivo activity against Staphyococcal aureus inmouse models, suggesting a novel approach to the development of noveltherapeutics. Six of these SMAMPs have been tested and demonstrated tokill P. falciparum parasites in culture with a range of IC₅₀s from 50 nMto 3 μM.

The present approach has several advantages. Anti-microbial peptideshave remained an effective weapon against bacterial infection overevolutionary time indicating that their mechanism of action thwartsbacterial responses that lead to resistance against toxic substances.This premise is supported by direct experimental data showing that noappreciable resistance to the action of the anti-microbial peptidesoccurs after multiple serial passages of bacteria in the presence ofsub-lethal concentrations of the peptides. Thus, targeting parasitemembranes rather than proteins represents a highly innovative and novelapproach to treating parasitic diseases and distinguishes the presentinvention from most others in this field.

To more fully evaluate the effects of SMAMP inhibitors on parasitegrowth through an entire life cycle, cytotoxic/cytostatic growth assaysare performed. A synchronized population of parasites can be pulsed withthe active SMAMPs for 8 hours during the ring, trophozoite, or schizontstages. The inhibitors can then removed by washing parasites and thenparasites can be allowed to finish their cycle. To estimate successfulparasite growth, a quantitative growth assay using luciferase expressingparasites can be used. The static effects can be differentiated fromtoxic effects and the timing of action of these compounds can bedetermined.

Morphological phenotypes arising from inhibition can be determined. Allinhibitors can be evaluated using P. falciparum parasites in a culturemodel of the erythrocytic cycle. Phenotypes for all parasite treatmentscan be analyzed using Giemsa staining and standard light microscopy.After determining the timing of parasite death, time lapseDIC/fluorescent microscopy can be used to determine that after additionof SMAMPs, the plasma membrane becomes compromised. P. falciparumparasites expressing cytoplasmic GFP can be used to allow for thevisualization of leakage of cytoplasmic contents after addition ofSMAMPs.

To investigate the potential for parasites to develop resistance againstthe antiparasitic activity of the AMP compounds, P. falciparum can beserially passaged in 0.25×EC₅₀, 0.5×EC₅₀ and the EC₅₀ concentrations ofthe top three AMP compounds. Resulting EC₅₀ values can be determined ateach passage for each inhibitor. As a control, parallel cultures canalso be exposed to 0.5 EC₅₀ concentrations of the antifolate WR99210and/or pyrimethamine, two well established anti-parasitic agents forwhich resistance has been reported. If parasites that are resistant toSMAMPs are generated, tiling microarrays (REF) can be used to helpdetermine any genes that contribute to resistance.

SMAMPs can be designed that can be used to probe mechanisms of actionand resistance, and compounds that are active in vivo can be obtained. Avery good correlation between the toxicity to mammalian cells and theoverall hydrophobicity of the molecule has been observed. The activityagainst a particular bacterium has correlated with the overallamphiphilicity of the molecule as well as hydrophobicity, so long as thecharge of the molecule was kept constant.

Example 22 Anti-protozoan Activity vs a Malarial Parasite

Seven compounds with diverse structures were screened in vitro againstthe malarial agent Plasmodium falciparum. P. falciparum is a protozoanparasite and is the infectious agent for the most prevalent and deadlyforms of malaria. It accounts for 80% of all human malarial infectionsand 90% of deaths. More than 120 million clinical cases of malaria andbetween 1 to 1.5 million deaths occur worldwide every year. There is novaccine for malaria and current therapies are plagued by rapidresistance which has become endemic in certain regions of the world.Several anti-microbial peptides possess anti-parasitic activities andappear to kill the parasites by interacting with the plasma membranecausing excessive permeability, lysis and death. Specificity for theparasite versus mammalian host cells is attributed to differences inphospholipid content and the lack of cholesterol in the protozoanmembrane.

Anti-parasitic activities were measured in vitro using a human red bloodcell assay. A single P. falciparum organism typically infects anerythrocyte and produces 24 progeny within 48 hours following infection.The progeny are released and rapidly infect neighboring red blood cells.The seven compounds (Table 1) were first screened at a singleconcentration and 6 of the 7 compounds killed P. falciparum progeny at a10 μM concentration. Four of the active compounds were tested further todetermine IC₅₀ and IC₁₀₀ values, or minimum concentrations resulting in50% and 100% killing, respectively. Observations were also made duringthe 48 hour incubation period to assess the susceptibility of theparasite during lifecycle stages inside and outside the hosterythrocyte. Two compounds, Compound 116 and Compound 107 possess sub-μMkilling activities and Compound 116 potently kills with an IC₅₀ of 0.05μM. Observations made during the infection cycle revealed that onlyparasitic organisms inside the erythrocyte were visible in the presenceof active compounds and no extra-cellular organisms were apparent.Together, these data indicate that the compounds are rapidly killing theprotozoa between the time of release and prior to re-infection. One goalof targeting parasite membranes, rather than proteins or metabolicpathways, represents a highly innovative and novel strategy for treatingparasitic diseases and distinguishes this approach from most others inthis field.

TABLE 1 Susceptibility of P. falciparum to compounds % Kill IC₅₀ IC₁₀₀Compound @ 10 μM (μM) (μM) 116 100 0.050 0.850 107 100 0.200 0.850 102100 1.5 3.5 103 100 0.200 1.5 101 100 NT NT 108 100 NT NT 102 <10 NT NT

Example 23 Anti-Malarial Activity

Several compounds were screened in cultures of P. falciparum at aconcentration of 1.0 or 1.5 μM and showed strong efficacy. Of thecompounds tested, Compounds 106 and 107 showed the best results.Compound 106 had an IC₅₀ in 3D7 cells of 150 nM with a cytotoxicity ofabout 40-50 μM in human HepG2 cells. Compound 107 had an IC₅₀ in 3D7cells of 275 nM with a cytotoxicity of about 50-100 μM in human HepG2cells. Parasite killing generally took place between 6 to 9 hours (datanot shown). Neither compound, however, was hemolytic as determined bytreatment of uninfected red blood cells using a standard absorbanceassay for hemoglobin release (data not shown). In addition, bothcompounds disrupted food vacuoles as assayed by parasites expressing amarker for the food vacuole (plasmepsin II-YFP), with food vacuoleintregrity measured by standard fluorescence microscopy.

Example 24 Anti-Malarial Activity

Compounds 106 and 107 were also screened in cultures of P. falciparum3D7 and DD2 and compared to chloroquine. Flow cytometry was used forquantitation of parasitemia using SYOX Green on an LSRII. The resultsare shown in Table 2.

TABLE 2 Compound IC₅₀ (3D7) IC₅₀ (DD2) chloroquine  20 nM  80 nMCompound 107 275 nM 200 nM Compound 106 150 nM 100 nMThe DD2 strain of P. falciparum is 4 times as resistant to chloroquineas the 3D7 strain. Both Compounds 106 and 107 were effective in strainDD2. Thus, these compounds are effective in chloroquire-sensitive and/orchloroquire-resistant strains.

Example 25 Anti-Malarial Activity

Numerous compounds were initially screened using a high throughputquantitative parasite growth assay that makes use of a strain ofparasites expressing a cytoplasmic firefly luciferase (obtained from Dr.Kirk Deitsch, Cornell Medical College). These parasites were transfectedwith a vector containing the firefly luciferase gene using the malarialHRPII promoter. To grow parasites, culture dishes ranging from 96 wellplates to 30 ml dishes were used. The 3D7 strain of P. falciparum forassays and transfections was primarily used because it has become thestandard chloroquine sensitive reference strain and was used for thegenome sequencing project. Parasites were cultured in human RBCs underan atmosphere of 5% O₂/7% CO₂/88% N₂ in RPMI 1640 medium supplementedwith 25 mM Hepes, 30 mg/L hypoxanthine, 0.225% (w/v) NaHCO₃ and 0.5%(w/v) Albumax II (Life Technologies, Grand Island, N.Y.). Parasitegrowth was normally synchronized by a combination of serial D-sorbitoltreatment for selection of ring stage parasites followed by selectivepurification of mature schizonts using a Super Macs II magneticseparator (Miltenyi Biotec).

A standard luminescent readout was used to measure the growth ofparasites. Parasites were grown under normal conditions, lysed in thepresence of the luminescence reagents (Bright Glo, Promega) and thenmeasured. To initially test for growth, luciferase expressing parasiteswere synchronized using serial sorbitol treatments and then parasitemia,the percentage of RBCS infected with parasites, was adjusted usinguninfected RBCs. 100 μl of total media was used in a 96 well format.Parasitized RBCs were incubated in 96 well plates at 37° C. and gassedwith 5% CO₂, 5% O₂, 90% N₂. Parasites were allowed to grow forapproximately 60 hours, until they successfully divided, ruptured andreinvaded new RBCs. At 10-15 hours post invasion, the cells were lysed,and luciferase levels were measured using an Analyst HT luminometer(Molecular Devices). Results are shown in Table 3.

TABLE 3 Compound IC₅₀ μM Artesunate 0.009 Compound 106 1.153 Compound118 0.364 Compound 119 1.858 Compound 110 0.584 Compound 117 0.301Compound 104 >10 Compound 111 0.587 Compound 113 0.241 Compound 112 >10Compound 120 0.604 Compound 121 1.505 Compound 114 >10 Compound 1025.376 Compound 103 0.783 Compound 107 0.314 Compound 116 0.318 Compound101 0.308 Compound 122 0.260 Compound 123 1.366 Compound 124 1.582Compound 129 0.832 Compound 128 1.725 Compound 127 1.765 Compound 1261.420 Compound 125 0.286 Compound 130 2.559 Compound 131 0.235 Compound132 0.236 Compound 133 2.028 Compound 134 2.438 Compound 135 0.108Compound 136 0.958 Compound 137 0.604 Compound 138 0.213 Compound 1391.169 Compound 140 1.674 Compound 142 0.063 Compound 154 0.200 Compound149 0.357 Compound 141 1.344 Compound 143 0.258 Compound 144 3.399Compound 145 0.369 Compound 146 0.127 Compound 155 0.535 Compound 1520.783 Compound 153 0.925 Compound 150 6.608 Compound 151 2.784 Compound147 0.221 Compound 148 0.704 Compound 156 0.107

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference (including, but not limitedto, journal articles, U.S. and non-U.S. patents, patent applicationpublications, international patent application publications, gene bankaccession numbers, and the like) cited in the present application isincorporated herein by reference in its entirety.

1-375. (canceled)
 376. A compound of Formula III:Q-X—Z—X-Q wherein: Z is

or phenyl; each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4; each X is, independently, O, S, or N; each R¹ is, independently, H,CF₃, C(CH₃)₃, halo, or OH; each R³ is, independently, H, —NH—R²,—(CH₂)_(r)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R² is, independently, H,or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R⁴is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and each R⁵ is, independently, H or CF₃; or a pharmaceuticallyacceptable salt thereof.
 377. A method of treating malaria in an animalor killing or inhibiting the growth of a Plasmodium species comprisingadministering to the animal a therapeutically effective amount of acompound of Formula III or contacting the species with an effectiveamount of a compound of Formula III:Q-X—Z—X-Q wherein: Z is

or phenyl; each Q is, independently,

or —C(═O)—(CH₂)_(b)—NH—C(═NH)—NH₂, where each b is, independently, 1 to4; each X is, independently, O, S, or N; each R¹ is, independently, H,CF₃, C(CH₃)₃, halo, or OH; each R³ is, independently, H, —NH—R²,—(CH₂)_(r)—NH₂, —NH₂, —NH—(CH₂)_(w)—NH₂, or

where each r is, independently, 1 or 2, each w is, independently, 1 to3, and each y is, independently, 1 or 2; each R² is, independently, H,or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R⁴is, independently, H, —NH—C(═O)—(CH₂)_(p)—NH—C(═NH)—NH₂ or

where each p is, independently, 1 to 6, and each q is, independently, 1or 2; and each R⁵ is, independently, H or CF₃; or a pharmaceuticallyacceptable salt thereof.
 378. A compound of Formula VIII:

wherein: D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and each X is, independently, O or S; or a pharmaceutically acceptablesalt thereof.
 379. A method of treating malaria in an animal or killingor inhibiting the growth of a Plasmodium species comprisingadministering to the animal a therapeutically effective amount of acompound of Formula VIII or contacting the species with an effectiveamount of a compound of Formula VIII:

wherein: D is

each B is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4,

and each X is, independently, O or S; or a pharmaceutically acceptablesalt thereof.
 380. A compound of Formula I:

wherein: X is C(R⁷)C(R⁸), C(═O), N(R⁹), O, S, S(═O), or S(═O)₂; R⁷, R⁸,and R⁹ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, oraromatic group; R¹ and R² are, independently, H, C₁-C₈alkyl,C₁-C₈alkoxy, halo, OH, haloC₁-C₈alkyl, or CN; R³ and R⁴ are,independently, carbocycle(R⁵)(R⁶); each R⁵ and each R⁶ are,independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, aromaticgroup, heterocycle, or the free base or salt form of —(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or a pharmaceutically acceptable saltthereof.
 381. A method of treating malaria in an animal or killing orinhibiting the growth of a Plasmodium species comprising administeringto the animal a therapeutically effective amount of a compound ofFormula I or contacting the species with an effective amount of acompound of Formula I:

wherein: X is C(R⁷)C(R⁸), C(═O), N(R⁹), O, S, S(═O), or S(═O)₂; R⁷, R⁸,and R⁹ are, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, oraromatic group; R¹ and R² are, independently, H, C₁-C₈alkyl,C₁-C₈alkoxy, halo, OH, haloC₁-C₈alkyl, or CN; R³ and R⁴ are,independently, carbocycle(R⁵)(R⁶); each R⁵ and each R⁶ are,independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo, OH, CF₃, aromaticgroup, heterocycle, or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or a pharmaceutically acceptable saltthereof.
 382. A compound of Formula II:

wherein: X is O or S; each Y is, independently, O, S, or N; each R¹ is,independently, H, 5- or 6-membered heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each R¹ is, independently, together with Y a5- or 6-membered heterocycle; each R² is, independently, H, CF₃,C(CH₃)₃, halo, or OH; and each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.
 383. A method of treatingmalaria in an animal or killing or inhibiting the growth of a Plasmodiumspecies comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula II or contacting the specieswith an effective amount of a compound of Formula II:

wherein: X is O or S; each Y is, independently, O, S, or N; each R¹ is,independently, H, 5- or 6-membered heterocycle, or the free base or saltform of —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each R¹ is, independently, together with Y a5- or 6-membered heterocycle; each R² is, independently, H, CF₃,C(CH₃)₃, halo, or OH; and each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.
 384. A compound of Formula IV:

wherein: G is

each X is, independently, O or S; each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R²is, independently, H, C₁-C₈alkyl, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R³ is, independently, H, CF₃, C(CH₃)₃, halo,or OH; and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.
 385. A method of treatingmalaria in an animal or killing or inhibiting the growth of a Plasmodiumspecies comprising administering to the animal a therapeuticallyeffective amount of a compound of Formula IV or contacting the specieswith an effective amount of a compound of Formula IV:

wherein: G is

each X is, independently, O or S; each R¹ is, independently,

or the free base or salt form of —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; each R²is, independently, H, C₁-C₈alkyl, or the free base or salt form of—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R³ is, independently, H, CF₃, C(CH₃)₃, halo,or OH; and each R⁴ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.
 386. A compound of Formula V:

wherein: each X is, independently, O, S, or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is,independently, 1 or 2; each R² is, independently, H, halo, CF₃, orC(CH₃)₃; and each V² is H, and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; or a pharmaceutically acceptable saltthereof, provided that the compound is not: a)

b)

or c)


387. A method of treating malaria in an animal or killing or inhibitingthe growth of a Plasmodium species comprising administering to theanimal a therapeutically effective amount of a compound of Formula IV orcontacting the species with an effective amount of a compound of FormulaIV:

wherein: each X is, independently, O, S, or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each p is,independently, 1 or 2; each R² is, independently, H, halo, CF₃, orC(CH₃)₃; and each V² is H, and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; or a pharmaceutically acceptable saltthereof.
 388. A compound of Formula VI:

wherein: each Y is, independently, O, S, or NH; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; and each R² is, independently, H, halo, CF₃,or C(CH₃)₃; or a pharmaceutically acceptable salt thereof.
 389. A methodof treating malaria in an animal or killing or inhibiting the growth ofa Plasmodium species comprising administering to the animal atherapeutically effective amount of a compound of Formula VI orcontacting the species with an effective amount of a compound of FormulaVI:

wherein: each Y is, independently, O, S, or NH; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; and each R² is, independently, H, halo, CF₃,or C(CH₃)₃; or a pharmaceutically acceptable salt thereof.
 390. A methodof treating malaria in an animal or killing or inhibiting the growth ofa Plasmodium species comprising administering to the animal atherapeutically effective amount of a compound of Formula VII orcontacting the species with an effective amount of a compound of FormulaVII:

wherein: each R¹ is, independently, H, C₁-C₈alkyl, C₁-C₈alkoxy, halo,OH, CF₃, or CN; each R² is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.